Wnt pathway modulators

ABSTRACT

The present invention relates to compounds of formula (I), 
     
       
         
         
             
             
         
       
         
         combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein 
         R 1  represents H; optionally substituted alkyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl and —N(C 1-3 alkyl) 2 ); —C(O)Oalkyl; haloalkyl; haloalkoxy; or -alkylaryl; 
         each R 2  independently represents H; optionally substituted alkyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl and —N(C 1-3 alkyl) 2 ); -alkylaryl; optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); optionally substituted heterocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl); —NHalkyl; —N(alkyl) 2 ; amino; hydroxyl; alkoxy or halo; 
         n represents  0, 1  or  2;    
         R 3  represents H or alkyl; 
         R 4  represents H or alkyl; 
         R 5  represents H or alkyl; 
         W and X each independently represent C═O; C═S; or CH 2 ; 
         Y represents aryl; heteroaryl; optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); or optionally substituted heterocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl); and 
         Z represents optionally substituted alkyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl and —N(C 1-3 alkyl) 2 ); aryl; heteroaryl; -alkylaryl;-alkylheteroaryl; optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); optionally substituted heterocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl); -alkylcarbocyclyl wherein carbocyclyl is optionally substituted (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and halo); -alkylheterocyclyl wherein heterocyclyl is optionally substituted (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl); -arylcarbocyclyl wherein carbocyclyl is optionally substituted (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and halo); or -arylheterocyclyl wherein heterocyclyl is optionally substituted (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl).

FIELD

The invention relates to WNT pathway modulators, processes for makingthem and methods for using them.

PRIORITY

This application claims priority from UK application GB 1322333.4, filed17 December 2013, the entire contents of which are incorportated hereinby cross-reference.

BACKGROUND

Wnt proteins are secreted glycoproteins acting as growth factors thatregulate various cellular functions include proliferation,differentiation, death, migration, and polarity, by activating multipleintracellular signaling cascades, including the β-catenin-dependent and-independent pathways. There are 19 Wnt members have been found inhumans and mice, and they exhibit unique expression patterns anddistinct functions during development. In humans and mice, the 10members of the Frizzled (Fz) family comprise a series of seven-passtransmembrane receptors that have been identified as Wnt receptors. Inaddition to Fz proteins, single-pass transmembrane proteins, such aslow-density lipoprotein receptor-related protein 5 (LRP5), LRP6,receptor tyrosine kinase (RTK)-like orphan receptor 1(Ror1), Ror2, andreceptor-like tyrosine kinase (Ryk), have been shown to function asco-receptors for Wnt signaling. Therefore, it has been assumedtraditionally that the binding of different Wnts to their specificreceptors selectively triggers different outcomes via distinctintracellular pathways.

Diverse Wnts, Wnt receptors, and downstream pathway all contribute tothe role of Wnt. These pathways all play a role in development, stemcell maintenance, cancer and metastasis.

In the absence of Wnt signaling, β-catenin is bound and phosphorylatedby a “destruction complex” containing the adenomatous polyposis coli(APC) and Axin proteins, as well as glycogen synthase kinase 3 (GSK3)and casein kinase I (CKI). Phosphorylated β-catenin is bound by the Fbox protein Slimb/β-TrCP and polyubiquitinated, leading to proteosomaldegradation. In addition, the complex acts to prevent nuclearlocalization of b-catenin. Upon Wnt binding to Frizzled (Fz) andlow-density lipoprotein-related proteins 5 and 6 (LRP5/6), GSK3, Axin,and other destruction complex components are recruited to the receptorcomplex. The function of the destruction complex is inhibited, andunphosphorylated β-catenin accumulates in the cytoplasm and eventuallytranslocates to the nucleus. There, it associates with TCF proteins,converting TCF from a repressor into an activator of Wnt-responsive genetranscription.

Wnt in Cancer & Stem Cell:

Deregulation of components of Wnt/β-catenin signaling is implied in awide spectrum of diseases including degenerative diseases, metabolicdiseases, and a number of cancers such as cervical, colon, breast,bladder, head and neck, gastric, lung, ovarian, prostate, thyroid,non-small-cell lung, as well as chronic lymphocytic leukemia,mesothelioma, melanoma, pancreatic adenocarcinoma, basal cell carcinoma,osteosarcoma, hepatocellular carcinoma, Wilm's tumor andmedulloblastoma.

Wnt signaling plays a role both during development, and within stem cellniches in adults. This is best established in skin, hematopoietic stemcells, mammary gland and in intestinal proliferation. For example, highlevel expression of DKK1, an inhibitor of Wnt signaling, blocks normalstem cell proliferation in mouse intestine, suggesting there is anessential role for Wnt signaling in maintenance of stem cells in thedigestive tract. Wnt roles in self renewal and expansion of stem cellshave also been demonstrated for embryonic and neural stem cells,suggesting that Wnt signaling may be a general requirement of stem cellmaintenance. Inhibition of Wnt signaling, e.g., by overexpression ofaxin or an extracellular Wnt-binding protein, sFRP, reduceshematopoietic stem cell (HSC) growth in vitro and the ability toreconstitute HSCs in vivo. Notably, while overexpression of activatedβ-catenin can expand HSC populations in culture for extended periods,two groups have reported that β-catenin is not required for HSC survivaland serial transplantation, supporting the proposal that there is moreto Wnt signaling than stabilization of β-catenin in stem cell survival.Diverse Wnts can regulate stem cell proliferation: Wnts 1, 5a, and 10bare able to stimulate expansion of HSC populations and Wnt5a actssynergistically with stem cell factor (SCF) to expand and promote selfrenewal of HSCs. The demonstration of a role for Wnt5a in HSC selfrenewal and its ability to synergize with stem cell factor isparticularly interesting because Wnt5a often acts in a β-cateninindependent manner. While Wnt signaling is critical for stem cellmaintenance, it may therefore be via signaling pathways distinct from orin parallel to the β-catenin pathway.

Fibrosis:

Wnt/β-catenin signaling pathway is essential to embryonic development ingeneral and organ morphogenesis, so it is not surprising thatdysregulation of this pathway in adult has been linked to fibroblastbiology and fibrosis. It has been demonstrated that Wnt/β-cateninsignaling play a role in severe fibrotic diseases, such as pulmonaryfibrosis, liver fibrosis, skin fibrosis and renal fibrosis.

Others:

Dysregulation of Wnt/β-catenin signaling contributes to the developmentof diabetic retinopathy by inducing retinal inflammation, vascularleakage, and neovascularization.

The binding of Wnt proteins to plasma membrane receptors on mesenchymalcells induces the differentiation of these cells into the osteoblastlineage and thereby supports bone formation. Wnts are also key signalingproteins in joint remodeling processes. Active Wnt signaling contributesto osteophyte formation and might have an essential role in the anabolicpattern of joint remodeling that is observed in ankylosing spondylitisand osteoarthritis. By contrast, blockade of Wnt signaling facilitatesbone erosion and contributes to catabolic joint remodeling, a processthat is observed in rheumatoid arthritis.

There is therefore a need for compounds that modulate and/or inhibit theWNT pathway so as to treat diseases associated with WNT activity.

Definitions

A measure of the binding of an inhibitor to and the subsequent releasefrom an enzyme is the “IC₅₀” value, which reflects the inhibitorconcentration, which at a given substrate concentration results in 50%enzyme activity.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. In one embodiment the subject is not a human.The subject may for example be a non-human mammal.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanbeing sought by a researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disease ordisorder being treated.

As used herein, the term “pharmaceutically acceptable” embraces bothhuman and veterinary use: For example the term “pharmaceuticallyacceptable” embraces a veterinarily acceptable compound or a compoundacceptable in human medicine and health care. In one embodiment, humanmedicine and health care is excluded.

Throughout the description and the claims the expression “alkyl”, unlessspecifically limited, denotes a C₁₋₁₂ alkyl group, suitably a C₁₋₆ alkylgroup, e.g. C₁₋₄ alkyl group. Alkyl groups may be straight chain orbranched. Suitable alkyl groups include, for example, methyl, ethyl,propyl (e.g. n-propyl and isopropyl), butyl (e.g n-butyl, iso-butyl,sec-butyl and tert-butyl), pentyl (e.g. n-pentyl), hexyl (e.g. n-hexyl),heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl). The expression “alk”,for example in the expressions “alkoxy”, “haloalkyl” and “thioalkyl”should be interpreted in accordance with the definition of “alkyl”.Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g.n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy(e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy (e.g. n-octoxy).Exemplary thioalkyl groups include methylthio-. Exemplary haloalkylgroups include fluoroalkyl e.g. CF₃.

The expression “alkenyl”, unless specifically limited, denotes a C₂₋₁₂alkenyl group, suitably a C₂₋₆ alkenyl group, e.g. a C₂₋₄ alkenyl group,which contains at least one double bond at any desired location andwhich does not contain any triple bonds. Alkenyl groups may be straightchain or branched. Exemplary alkenyl groups including one double bondinclude propenyl and butenyl. Exemplary alkenyl groups including twodouble bonds include pentadienyl, e.g. (1E, 3E)-pentadienyl.

The expression “alkynyl”, unless specifically limited, denotes a C₂₋₁₂alkynyl group, suitably a C₂₋₆ alkynyl group, e.g. a C₂₋₄ alkynyl group,which contains at least one triple bond at any desired location and mayor may not also contain one or more double bonds. Alkynyl groups may bestraight chain or branched. Exemplary alkynyl groups include propynyland butynyl.

The expression “alkylene” denotes a chain of formula —(CH₂)_(n)— whereinn is an integer e.g. 1-12, 1-6, 2-6 or 2-5, unless specifically limited.

The expression “cycloalkyl”, unless specifically limited, denotes aC₃₋₁₀ cycloalkyl group (i.e. 3 to 10 ring carbon atoms), more suitably aC₃₋₈ cycloalkyl group, e.g. a C₃₋₆ cycloalkyl group. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. A most suitable number of ringcarbon atoms is three to six.

The expression “cycloalkenyl”, unless specifically limited, denotes aC₃₋₁₀ cycloalkenyl group (i.e. 3 to 10 ring carbon atoms), suitably aC₅₋₁₀ cycloalkenyl group (i.e. 5 to 10 ring carbon atoms), more suitablya C₅₋₈ cycloalkenyl group e.g. a C₅₋₆ cycloalkenyl group. Exemplarycycloalkenyl groups include cyclopropenyl, cyclohexenyl, cycloheptenyland cyclooctenyl. A most suitable number of ring carbon atoms is five tosix.

The expression “carbocyclyl”, unless specifically limited, denotes anyring system in which all the ring atoms are carbon and which containsbetween three and twelve ring carbon atoms, suitably between three andten carbon atoms and more suitably between three and eight carbon atoms.Carbocyclyl groups may be saturated or partially unsaturated, but do notinclude aromatic rings. Examples of carbocyclyl groups includemonocyclic, bicyclic, and tricyclic ring systems, in particularmonocyclic and bicyclic ring systems. Other carbocyclyl groups includebridged ring systems (e.g. bicyclo[2.2.1]heptenyl). A specific exampleof a carbocyclyl group is a cycloalkyl group. A further example of acarbocyclyl group is a cycloalkenyl group.

The expression “heterocyclyl”, unless specifically limited, refers to acarbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms arereplaced by heteroatoms. The heteroatom(s) are commonly selected from N,S and O. A specific example of a heterocyclyl group is a cycloalkylgroup (e.g. cyclopentyl or more particularly cyclohexyl) wherein one ormore (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms arereplaced by heteroatoms selected from N, S or O. Exemplary heterocyclylgroups containing one hetero atom include pyrrolidine, tetrahydrofuranand piperidine, and exemplary heterocyclyl groups containing two heteroatoms include morpholine and piperazine. A further specific example of aheterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group)wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1)ring atoms are replaced by heteroatoms selected from N, S and O. Anexample of such a group is dihydropyranyl (e.g.3,4-dihydro-2H-pyran-2-yl-). The heterocyclyl group may be linked toother part or parts of the molecule by a carbon ring atom or nitrogenring atom.

The expression “aryl”, unless specifically limited, denotes a C₆₋₁₂ arylgroup, suitably a C₆₋₁₀ aryl group, more suitably a C₆₋₈ aryl group.Aryl groups will contain at least one aromatic ring (e.g. one, two orthree rings). Aryl groups with multiple aromatic rings include fusedaromatic rings and aromatic rings connected to each other by one singlebond. An example of a typical aryl group with one aromatic ring isphenyl. An example of a typical aryl group with two fused aromatic ringsis naphthyl. An example of an aromatic group with two directly connectedaromatic rings is biphenyl.

The expression “heteroaryl”, unless specifically limited, denotes anaryl residue, wherein one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or3) ring atoms are replaced by heteroatoms, said heteroatoms commonlybeing selected from N, S and O, or else a 5-membered aromatic ringcontaining one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) ringatoms, said heteroatoms commonly selected from N, S and O. In someembodiments a heteroaryl group will have no ring heteroatoms other thannitrogen. Exemplary monocyclic heteroaryl groups having one heteroatominclude: five membered rings (e.g. pyrrole, furan, thiophene); and sixmembered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl andpyridin-4-yl). Exemplary monocyclic heteroaryl groups having twoheteroatoms include: five membered rings (e.g. pyrazole, oxazole,isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl,imidazol-2-yl imidazol-4-yl); and six membered rings (e.g. pyridazine,pyrimidine, pyrazine). Exemplary monocyclic heteroaryl groups havingthree heteroatoms include: 1,2,3-triazole, 1,2,4-triazole,1,2,3-oxadiazole and 1,2,4-oxadiazole. Exemplary monocyclic heteroarylgroups having four heteroatoms include tetrazole. Exemplary bicyclicheteroaryl groups include: indole (e.g. indol-6-yl), benzofuran,benzthiophene, quinoline, isoquinoline, indazole, benzimidazole,benzthiazole, quinazoline and purine. The heteraryl group may be linkedto other part or parts of the molecule by a carbon ring atom or nitrogenring atom.

The aforementioned aryl and heteroaryl groups may, where appropriate,optionally be substituted by one or more (e.g. 1, 2 or 3, suitably 1 or2) groups each independently selected from monovalent or multivalent(i.e. having valency greater than 1) functional groups. Suitablesubstituent groups include alkyl, alkenyl, alkynyl, haloalkyl, -alkoxy(e.g. OMe), cycloalkyl, alkenyloxy-, alkynyloxy-, alkoxyalkyl-, nitro,halogen (e.g. fluoro, chloro and bromo), cyano, hydroxyl, oxo,—C(O)-alkyl (e.g. COMe), C(O)OH, —C(O)Oalkyl (e.g. —C(O)OMe),—OC(O)alkyl (e.g. —OC(O)Me), —NH₂, —NHalkyl (e.g. —NHMe), —N(alkyl)₂(e.g. dimethylamino-), —C(O)NH₂, —C(O)NH(alkyl) (e.g. —C(O)NHMe),—NHC(O)alkyl (e.g. —NHC(O)Me), —C(NH)NH₂, thioalkyl (e.g. -thiomethyl),—SO₂alkyl (e.g. SO₂Me), —SOalkyl (e.g. —SOMe), —SO₂cycloalkyl and—SOcycloalkyl. More typically, substituents will be selected from alkyl(e.g. Me), fluoroalkyl (e.g. CF₃ and CHF₂), alkoxy (e.g. OMe), halogenand hydroxyl.

The expression “-alkylaryl”, unless specifically limited, denotes anaryl residue which is connected via an alkylene moiety e.g. aC₁₋₄alkylene moiety. An example of such a group is benzyl: PhCH₂—.

The term “halogen” or “halo” comprises fluorine (F), chlorine (Cl) andbromine (Br).

The term “amino” refers to the group —NH₂.

The term “oxo” refers to an oxygen atom which, together with the carbonatom which it substitutes, forms a carbonyl group C═O.

The term “-arylheterocyclyl” refers to a heterocyclyl residue which isconnected via an aryl moiety.

Stereoisomers:

All possible stereoisomers of the claimed compounds are included in thepresent invention.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Preparation and isolation of stereoisomers:

Where the processes for the preparation of the compounds according tothe invention give rise to a mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Pharmaceutically acceptable salts:

In view of the close relationship between the free compounds and thecompounds in the form of their salts or solvates, whenever a compound isreferred to in this context, a corresponding salt, solvate or polymorphis also intended, provided such is possible or appropriate under thecircumstances.

Salts and solvates of the compounds of formula (I) and physiologicallyfunctional derivatives thereof which are suitable for use in medicineare those wherein the counter-ion or associated solvent ispharmaceutically acceptable. However, salts and solvates havingnon-pharmaceutically acceptable counter-ions or associated solvents arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds and theirpharmaceutically acceptable salts and solvates.

Suitable salts according to the invention include those formed with bothorganic and inorganic acids or bases. Pharmaceutically acceptable acidaddition salts include those formed from hydrochloric, hydrobromic,sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic,oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic,oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for examplep-toluenesulfonic, benzenesulfonic, naphthalenesulfonic ornaphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic,cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy orhalo substituted cinnamic, including 4-methyl and 4-methoxycinnamicacid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or3-hydroxy-2-naphthoic), naphthaleneacrylic (for examplenaphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (forexample 1,4-benzenediacrylic), isethionic acids, perchloric, propionic,glycolic, hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic,saccharinic and trifluoroacetic acid. Pharmaceutically acceptable basesalts include ammonium salts, alkali metal salts such as those of sodiumand potassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine.

All pharmaceutically acceptable acid addition salt forms of thecompounds of the present invention are intended to be embraced by thescope of this invention.

Polymorph crystal forms:

Furthermore, some of the crystalline forms of the compounds may exist aspolymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e. hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention. Thecompounds, including their salts, can also be obtained in the form oftheir hydrates, or include other solvents used for theircrystallization.

Prodrugs:

The present invention further includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the desired therapeutically active compound. Thus, in thesecases, the methods of treatment of the present invention, the term“administering” shall encompass the treatment of the various disordersdescribed with prodrug versions of one or more of the claimed compounds,but which converts to the above specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Protective Groups:

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991, fully incorporatedherein by reference. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

As used herein, the term “composition” is intended to encompass aproduct comprising the claimed compounds in the therapeuticallyeffective amounts, as well as any product which results, directly orindirectly, from combinations of the claimed compounds.

Carriers and Additives for galenic formulations:

Carriers, which can be added to the mixture, include necessary and inertpharmaceutical excipients, including, but not limited to, suitablebinders, suspending agents, lubricants, flavorants, sweeteners,preservatives, coatings, disintegrating agents, dyes and coloringagents.

Thus, for liquid oral preparations, such as for example, suspensions,elixirs and solutions, suitable carriers and additives mayadvantageously include water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like; for solid oral preparationssuch as, for example, powders, capsules, gelcaps and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like.

Soluble polymers as targetable drug carriers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolyllysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, polyacticacid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Suitable binders include, without limitation, starch, gelatin, naturalsugars such as glucose or betalactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth or sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like.

Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

SUMMARY OF INVENTION

According to the invention there is provided a compound of formula (I),

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof wherein:

R₁ represents H; optionally substituted alkyl (wherein optionalsubstituents include one or more substituents each independentlyselected from C₁₋₆alkoxy, NH₂, —NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂);—C(O)Oalkyl; haloalkyl; haloalkoxy; or -alkylaryl;

each R₂ independently represents H; optionally substituted alkyl(wherein optional substituents include one or more substituents eachindependently selected from C₁₋₆alkoxy, NH₂, —NHC₁₋₃alkyl and—N(C₁₋₃alkyl)₂); -alkylaryl; optionally substituted carbocyclyl (whereinoptional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆haloalkoxy and halo); optionally substituted heterocyclyl (whereinoptional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl); —NHalkyl; —N(alkyl)₂; amino;hydroxyl; alkoxy or halo;

n represents 0, 1 or 2;

R₃ represents H or alkyl;

R₄ represents H or alkyl;

R₅ represents H or alkyl;

W and X each independently represent C═O; C═S; or CH₂;

Y represents aryl; heteroaryl; optionally substituted carbocyclyl(wherein optional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆haloalkoxy and halo); or optionally substituted heterocyclyl(wherein optional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl); and

Z represents optionally substituted alkyl (wherein optional substituentsinclude one or more substituents each independently selected fromC₁₋₆alkoxy, NH₂, —NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂); aryl; heteroaryl;-alkylaryl;-alkylheteroaryl; optionally substituted carbocyclyl (whereinoptional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆haloalkoxy and halo); optionally substituted heterocyclyl (whereinoptional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl); -alkylcarbocyclyl whereincarbocyclyl is optionally substituted (wherein optional substituentsinclude one or more substituents each independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy and halo); -alkylheterocyclylwherein heterocyclyl is optionally substituted (wherein optionalsubstituents include one or more substituents each independentlyselected from C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and—C(O)NHC₁₋₆alkyl); -arylcarbocyclyl wherein carbocyclyl is optionallysubstituted (wherein optional substituents include one or moresubstituents each independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy and halo); or -arylheterocyclyl wherein heterocyclyl isoptionally substituted (wherein optional substituents include one ormore substituents each independently selected from C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl).

Further, according to the invention there is provided a compound offormula (I),

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof wherein:

R₁ represents H; alkyl which is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂; —C(O)Oalkyl; haloalkyl; haloalkoxy; or-alkylaryl;

each R₂ independently represents H; alkyl which is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkoxy, NH₂, —NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂; -alkylaryl;carbocyclyl which is optionally substituted by one or more substituentseach independently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆haloalkoxy and halo; heterocyclyl which is optionally substituted byone or more substituents each independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl;—NHalkyl; —N(alkyl)₂; amino; hydroxyl; alkoxy or halo;

n represents 0, 1 or 2;

R₃ represents H or alkyl;

R₄ represents H or alkyl;

R₅ represents H or alkyl;

W and X each independently represent C═O; C═S; or CH₂;

Y represents aryl; heteroaryl; carbocyclyl which is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo; orheterocyclyl which is optionally substituted by one or more substituentseach independently selected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl; and

Z represents alkyl which is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂; aryl;heteroaryl;-alkylaryl;-alkylheteroaryl; carbocyclyl which is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo;heterocyclyl which is optionally substituted by one or more substituentseach independently selected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl; -alkylcarbocyclyl whereincarbocyclyl is optionally substituted by one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy andhalo; -alkylheterocyclyl wherein heterocyclyl is optionally substitutedby one or more substituents each independently selected from C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl; -arylcarbocyclylwherein carbocyclyl is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy and halo; or -arylheterocyclyl wherein heterocyclyl isoptionally substituted by one or more substituents each independentlyselected from C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and—C(O)NHC₁₋₆alkyl.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1: A bar chart illustrating inhibition of the activity of mammalianporcupine by Compound 51 and Compound 110.

FIG. 2: A graph illustrating efficacy of Compound 51 on the MMTV-Wnt1mouse model.

FIG. 3: A graph illustrating efficacy data of Compound 110 in theMMTV-Wnt1 mouse model.

FIG. 4: Images illustrating inhibition of Palmitoylation of Wnt3a byCompound 51.

FIGS. 5 to 7: Images and graphs showing results of the Soft Agar Assay.FIG. 5 shows the results for Cell line AsPC-1 treated with Compound 51.FIG. 6 shows the results for Cell line HPAF-II treated with Compound 51.FIG. 7 shows the results for Cell line CFPAC-1 treated with Compound 51.

DETAILED DESCRIPTION

According to the invention there are provided compounds of formula (I),

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof wherein:

R₁ represents H; alkyl which is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂; —C(O)Oalkyl; haloalkyl; haloalkoxy; or-alkylaryl;

each R₂ independently represents H; alkyl which is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkoxy, NH₂, —NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂; -alkylaryl;carbocyclyl which is optionally substituted by one or more substituentseach independently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆haloalkoxy and halo; heterocyclyl which is optionally substituted byone or more substituents each independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl;—NHalkyl; —N(alkyl)₂; amino; hydroxyl; alkoxy or halo;

n represents 0, 1 or 2;

R₃ represents H or alkyl;

R₄ represents H or alkyl;

R₅ represents H or alkyl;

W and X each independently represent C═O; C═S; or CH₂;

Y represents aryl; heteroaryl; carbocyclyl which is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo; orheterocyclyl which is optionally substituted by one or more substituentseach independently selected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl; and

Z represents alkyl which is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂; aryl; heteroaryl;-alkylaryl;-alkylheteroaryl; carbocyclyl which is optionally substituted by one ormore substituents each independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo; heterocyclyl whichis optionally substituted by one or more substituents each independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and—C(O)NHC₁₋₆alkyl; -alkylcarbocyclyl wherein carbocyclyl is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo;-alkylheterocyclyl wherein heterocyclyl is optionally substituted by oneor more substituents each independently selected from C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl; -arylcarbocyclylwherein carbocyclyl is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo; or -arylheterocyclyl whereinheterocyclyl is optionally substituted by one or more substituents eachindependently selected from C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyland —C(O)NHC₁₋₆alkyl.

In one embodiment, any one or more of, optionally all of, the followingcompounds are excluded from the scope of Formula (I):

In the context of variable Y, the term “aryl” is understood to mean“arylene” (e.g. “phenyl” is understood to mean “phenylene” (i.e. C₆H₄))because Y is a linking group, not a terminal group. The terms for otherY rings (e.g. heteroaryl) are to be construed likewise. When Y isreferred to as being unsubstituted, this is understood to mean no othersubstituents other than Z and NR₅. When Y is referred to as beingmonosubstitued, this is understood to mean one substituent other than Zand NR₅.

When R₁ represents alkyl which is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂ exemplary substituents include methoxy,—NH₂, —NHmethyl and —NH(methyl)₂. Examples include C₁₋₆ alkyl (e.g.unsubstituted C₁₋₆alkyl), for example methyl, ethyl, propyl (e.g.n-propyl, isopropyl), butyl (e.g. n-butyl, iso-butyl, sec-butyl,tert-butyl), pentyl (e.g. n-pentyl) and hexyl (e.g. n-hexyl). ExemplaryC₁₋₆ alkyl groups are methyl and ethyl, particularly methyl.

When R₁ represents —C(O)Oalkyl, examples include —C(O)OC₁₋₆alkyl such as—C(O)OMe, —C(O)OEt, —C(O)OPr and —C(O)OiPr. A specific example is—C(O)OMe.

When R₁ represents haloalkyl, examples include C₁₋₆haloalkyl such asCH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, CHFCH₃ and CF₂CH₃. A specificexample is CF₃.

When R₁ represents haloalkoxy, examples include C₁₋₆haloalkoxy such asOCF₃.

When R₂ represents alkyl which is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂, exemplary substituents include methoxy,—NH₂, —NHmethyl and —NH(methyl)₂. Examples include C₁₋₆ alkyl (e.g.unsubstituted C₁₋₆alkyl), for example methyl, ethyl, propyl (e.g.n-propyl, isopropyl), butyl (e.g. n-butyl, iso-butyl, sec-butyl,tert-butyl), pentyl (e.g. n-pentyl) and hexyl (e.g. n-hexyl). Anexemplary C₁₋₆ alkyl group is methyl.

When R₂represents—alkylaryl, examples include benzyl.

When R₂ represents carbocyclyl which is optionally substituted by one ormore substituents each independently selected from C₁₋₆alkyl (e.g.methyl), C₁₋₆alkoxy (e.g. methoxy), C₁₋₆haloalkyl (e.g. fluoromethylsuch as trifluoromethyl), C₁₋₆haloalkoxy (e.g. fluoromethoxy such astrifluoromethoxy) and halo (e.g. fluoro, e.g. chloro), examples includeC₃-C₆ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. Substituted examples include cyclohexyl substituted bymethyl.

When R₂ represents heterocyclyl which is optionally substituted by oneor more substituents each independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl, Y mayrepresent heterocyclyl which is optionally substituted by C₁₋₆ alkyl(such as methyl). Examples include monocyclic heterocyclyl. Theheterocyclyl group may be unsubstituted or may have for example one ortwo (e.g. one) substituent (e.g. one methyl group). Examples includepiperidinyl, morpholinyl, pyrrolidinyl, 4,5-dihydropyrazolyl and4,5-dihydroisoxazolyl. A specific example is pyrrolidinyl.

When R₂ represents —NHalkyl, examples include —NHMe, NHEt, NHPr andNHiPr, in particular NHMe.

When R₂ represents —N(alkyl)₂, examples include —N(Me)₂.

When R₂ represents alkoxy, examples include methoxy and ethoxy,especially methoxy.

When n represents 1, examples of —(CHR₂)_(n)— include —CH₂— and—CH(CH₃)—.

When n represents 2, examples of —(CHR₂)_(n)— include —CH₂—CH₂—,—CH₂CH(CH₃)—, —CH(CH₃)CH₂— and —CH(CH₃)—CH(CH₃)—. An example of a—(CHR₂)₂— group is —CH₂—CH₂—.

When R₃ represents alkyl, examples include C₁₋₆ alkyl such as methyl,ethyl, propyl (e.g. n-propyl, isopropyl), butyl (e.g. n-butyl,iso-butyl, sec-butyl, tert-butyl), pentyl (e.g. n-pentyl) and hexyl(e.g. n-hexyl). An exemplary C₁₋₆ alkyl group is methyl.

When R₄ represents alkyl, examples include C₁₋₆ alkyl, for examplemethyl, ethyl, propyl (e.g. n-propyl, isopropyl), butyl (e.g. n-butyl,iso-butyl, sec-butyl, tert-butyl), pentyl (e.g. n-pentyl) and hexyl(e.g. n-hexyl). An exemplary C₁₋₆ alkyl group is methyl.

When R₅ represents alkyl, examples include C₁₋₆ alkyl such as methyl,ethyl, propyl (e.g. n-propyl, isopropyl), butyl (e.g. n-butyl,iso-butyl, sec-butyl, tert-butyl), pentyl (e.g. n-pentyl) and hexyl(e.g. n-hexyl). An exemplary C₁₋₆ alkyl group is methyl.

When Y represents aryl, examples include optionally substituted phenyl.Exemplary substituents include one or more (e.g. one or two, especiallyone) substituents each independently selected from C₁₋₆ alkyl (such asmethyl), C₁₋₆alkoxy (such as methoxy), halo and C₁₋₆haloalkyl (such asfluoroemethyl, e.g. trifluoromethyl). Examples include unsubstitutedphenyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl andtrifluoromethylphenyl. Specific examples include unsubstituted phenyl.Specific examples also include methylphenyl, methoxyphenyl,fluorophenyl. Z and NR₅ may be positioned on the phenyl ring at the 1-and 4-positions relative to each other (i.e. Z and NR₅ have a pararelationship).

When Y represents heteroaryl, examples include monocyclic (e.g. 5 and 6membered) and bicyclic (e.g. 9 and 10 membered) heteroaryl rings,especially monocyclic heteroaryl rings, particularly 6-memberedmonocyclic heteroaryl rings. Examples of monocyclic heteroaryl maycomprise one, two or three ring heteroatoms (e.g. one or two, e.g. one)including one or two nitrogen atoms (e.g. one or e.g. two) andoptionally an oxygen or sulphur atom. Exemplary 5-membered monocyclicheteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl. WhenY is 5-membered monocyclic heteroaryl, Z and NR₅ may be positioned onthe ring at non-adjacent ring atoms. Exemplary 6-membered monocyclicheteroaryl groups include pyridinyl. Exemplary 6-membered monocyclicheteroaryl groups also include pyridazinyl, pyrimidinyl and pyrazinyl.When Y is 6-membered monocyclic heteroaryl, Z and NR₅ may be positionedon the ring at 1- and 4-positions relative to each other (i.e. Z and NR₅have a para relationship). The aforementioned heteroaryl group mayeither by unsubstituted or may be substituted by one or more (e.g. oneor two, particularly one) substituents. Exemplary substituents areindependently selected from C₁₋₆alkyl (such as methyl), C₁₋₆alkoxy (suchas methoxy), halo (such as fluoro) and C₁₋₆haloalkyl (such asfluoromethyl, e.g. trifluoromethyl). When Y is unsubstituted heteroaryl,examples include isoxazolyl (e.g. isoxazolyl-5-yl (wherein NR₅ is at the5-position and Z is at the 3-position) and isoxazolyl-3-yl (wherein NR₅is at the 3-position and Z is at the 5-position), especiallyisoxazol-5-yl), oxadiazolyl, pyridinyl (e.g. pyridin-2-yl orpyridin-3-yl), pyridazinyl (e.g. pyridazin-3-yl), pyrimidinyl (e.g.pyrimidin-3-yl), pyrazinyl (e.g. pyrazin-2-yl). When Y is substitutedheteroaryl, Y may for example be substituted by methyl or fluoro. When Yis substituted heteroaryl, examples include methylpyridinyl,fluoropyridinyl, methylpyridazinyl, methylpyrazinyl methylpyrimidinyland 1-methylpyrazolyl.

When Y represents carbocyclyl which is optionally substituted by one ormore substituents each independently selected from C₁₋₆alkyl (e.g.methyl), C₁₋₆alkoxy (e.g. methoxy), C₁₋₆haloalkyl (e.g. fluoromethylsuch as trifluoromethyl), C₁₋₆haloalkoxy (e.g. fluoromethoxy) and halo(e.g. fluoro, e.g. chloro), Y may represent carbocyclyl which isoptionally substituted by C₁₋₆alkyl. Examples include monocycliccarbocyclyl which is optionally substituted by C₁₋₆alkyl (such asmethyl). Examples of carbocyclyl include C₃₋₈cycloalkyl (e.g.cyclohexyl) and C₅₋₈cycloalkenyl (e.g. cyclohexenyl). The carbocycylring is optionally substituted by one, two or three independentlyselected substituents (e.g. one or two, especially one, e.g. one methylgroup). When Y represents carbocyclyl, Y may represent C₃₋₈cycloalkyl,such as C₅₋₆cycloalkyl. A specific example is cyclohexyl. When Y is6-membered carbocyclyl, Z and NR₅ are may be positioned on thecarbocyclyl ring at the 1- and 4-positions relative to each other.

When Y represents heterocyclyl which is optionally substituted by one ormore substituents each independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl, Y mayrepresent heterocyclyl which is optionally substituted by C₁₋₆ alkyl(such as methyl). Examples include monocyclic heterocyclyl. Theheterocyclyl group may be unsubstituted or may have for example one ortwo (e.g. one) substituent (e.g. one methyl group). Examples includepiperidinyl, morpholinyl, pyrrolidinyl, 4,5-dihydropyrazolyl and4,5-dihydroisoxazolyl. Specific examples include 4,5-dihydroisoxazolyl(e.g. 4,5-dihydroisoxazol-5-yl) and piperidinyl (e.g. piperidin-4-yl).When Y is 6-membered heterocyclyl, Z and NR₅ may be positioned on theheterocyclyl ring at the 1- and 4-positions relative to each other. WhenY represents heterocyclyl, in one embodiement Z does notrepresent—alkylaryl.

When Z represents alkyl which is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂, exemplary substituents include methoxy,—NH₂, —NHmethyl and —NH(methyl)₂. Examples include C₁₋₆alkyl (e.g.unsubstituted C₁₋₆alkyl), for example methyl, ethyl, propyl (e.g.n-propyl, isopropyl), butyl (e.g. n-butyl, iso-butyl, sec-butyl,tert-butyl), pentyl (e.g. n-pentyl) and hexyl (e.g. n-hexyl). Examplesalso include C₃₋₆alkyl (e.g. unsubstituted C₃₋₆alkyl), for examplepropyl (e.g. n-propyl, isopropyl), butyl (e.g. n-butyl, iso-butyl,sec-butyl, tert-butyl), pentyl (e.g. n-pentyl) and hexyl (e.g. n-hexyl).Exemplary C₁₋₆ alkyl groups are methyl and tert-butyl.

When Z represents aryl, examples include optionally substituted phenyl.Exemplary substituents include one or more (e.g. one or two, especiallyone) substituents each independently selected from fluoro, chloro,bromo, amino, methoxy, methyl, haloalkyl (e.g. fluoromethyl such astrifluoromethyl), —COOH, —C(O)NMe₂, dimethylamino and —NHC(O)Me.Examples include unsubstituted phenyl. Substituted examples includefluorophenyl (e.g. 2-fluorophenyl, 3-fluorophenyl and 4-fluorophenyl),chlorophenyl (e.g. 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and3,4-dichlorophenyl), bromophenyl (e.g. 2-bromophenyl, 3-bromophenyl and4-bromophenyl), aminophenyl (e.g. 2-aminophenyl, 3-aminophenyl,4-aminophenyl), methoxyphenyl (e.g. 2-methoxyphenyl, 3-methoxyphenyl and4-methoxyphenyl), methylphenyl (e.g. 2-methylphenyl, 3-methylphenyl and4-methylphenyl), fluoromethylphenyl (e.g. 3-trifluoromethylphenyl and4-trifluoromethylphenyl), carboxyphenyl (e.g. 3—(COOH)-phenyl),3—(C(O)NMe₂)-phenyl), 3-dimethylaminophenyl and 3-(NHC(O)Me)-phenyl.

When Z represents heteroaryl, examples include monocyclic (e.g. 5 and 6membered) and bicyclic (e.g. 9 and 10 membered) heteroaryl rings,especially monocyclic rings. Examples of monocyclic heteroaryl compriseone, two or three ring heteroatoms (e.g. one or two, e.g. one) includingone or two nitrogen atoms (e.g. one or e.g. two) and optionally anoxygen or sulphur atom. Exemplary 5-membered monocyclic heteroarylgroups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl. Exemplary6-membered monocyclic heteroaryl groups include pyridinyl. Exemplary6-membered monocyclic heteroaryl groups also include pyridazinyl,pyrimidinyl and pyrazinyl. The aforementioned heteroaryl group mayeither by unsubstituted or may be substituted by one or more (e.g. oneor two, particularly one) substituents. Exemplary substituents areindependently selected from methyl, fluoro, chloro, amino, halomethyl(e.g. fluoromethyl such as trifluoromethyl). Unsubstituted examplesinclude pyridinyl (e.g. pyridin-2-yl, pyridin-3-yl and pyridin-4-yl),pyrazinyl (e.g. pyrazin-2-yl), pyridazinyl (e.g. pyridazin-3-yl),pyrimidinyl (e.g. pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl),oxazolyl (e.g. oxazol-2-yl and oxazol-5-yl), thiazolyl (e.g.thiazol-2-yl and thiazole-5-yl) and pyrazolyl (e.g. pyrazol-1-yl).Substituted examples include chloropyridinyl (e.g. 4-chloropyridin-2-yl,5-chloropyridin-2-yl and 5-chloropyridin-3-yl), fluoropyridinyl (e.g.4-fluoropyridin-2-yl, 5-fluoropyridin-2-yl and 5-fluoropyridin-3-yl),methylpyridinyl (e.g. 2-methylpyridin-5-yl, 6-methylpyridin-2-yl and5-methylpyridin-3-yl), fluoromethylpyridinyl (e.g.5-trifluoromethylpyridin-3-yl), aminopyridinyl (e.g.5-aminopyridin-3-yl), methylpyrazinyl (e.g. 5-methylpyrazin-2-yl),methylthiazolyl (e.g. 2-methylthiazol-4-yl) and methylpyrazolyl (e.g.1-methylpyrazol-5-yl).

When Z represents—alkylaryl, examples include benzyl.

When Z represents -alkylheteroaryl (e.g. —CH₂-heteroaryl), examplesinclude—alkylpyrrolyl, -alkylpyrazolyl, -alkylimidazolyl,-alkyloxazolyl, -alkylisoxazolyl, -alkylthiazolyl, -alkylisothiazolyl,-alkyloxadiazolyl, -alkylthiadiazolyl, -alkylpyridinyl,-alkylpyridazinyl, -alkylpyrimidinyl and -alkylpyrazinyl.

When Z represents carbocyclyl which is optionally substituted by one ormore substituents each independently selected from C₁₋₆alkyl (e.g.methyl), C₁₋₆alkoxy (e.g. methoxy), C₁₋₆haloalkyl (e.g. fluoromethyl),C₁₋₆haloalkoxy (e.g. fluoromethoxy) and halo (e.g. fluoro, e.g. chloro),Z may represent carbocyclyl which is optionally substituted by C₁₋₆alkyl. Examples include monocyclic carbocyclyl which is optionallysubstituted by C₁₋₆ alkyl (such as methyl). Examples of carbocyclylinclude C₃₋₈cycloalkyl (e.g. cyclohexyl) and C₅₋₈cycloalkenyl (e.g.cyclohexenyl). The carbocycyl ring is optionally substituted by one, twoor three substituents (e.g. one or two, especially one, e.g. one methylgroup). When Z represents carbocyclyl, Z may represent C₃₋₈cycloalkyl,such as C₅₋₆cycloalkyl. A specific example is cyclohexyl.

When Z represents heterocyclyl which is optionally substituted by one ormore substituents each independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl, —C(O)NHC₁₋₆alkyl C₁₋₆alkyl(e.g. methyl), —C(O)OC₁₋₆alkyl (e.g. —C(O)Omethyl), —C(O)C₁₋₆alkyl (e.g.—C(O)methyl),—C(O)NHC₁₋₆alkyl (e.g. —C(O)NHmethyl), examples includeunsubstituted heterocyclyl and heterocyclyl with one or two (e.g. one)substituent. Examples include heterocyclyl groups containing onenitrogen atom (such as pyrrolidinyl and piperidinyl) or two nitrogenatoms (such as piperazinyl). Examples also include heterocyclyl groupscontaining one nitrogen atom and one oxygen atom(e.g. morpholinyl) orone sulfur atom (e.g. thiomorpholinyl). In one embodiment when Z issubstituted, a ring nitrogen atom is substituted. Substituted examplesinclude substituted piperazinyl, such as 4-substitued piperazinyl, e.g.4-Boc-piperazinyl, 4-(C(O)Me)-piperazinyl, 4-(C(O)NHEt)piperazinyl and4-methylpiperazinyl.

When Z represents—alkylcarbocyclyl (e.g. —CH₂-carbocyclyl) whereincarbocyclyl is optionally substituted by one or more substituents eachindependently selected from C₁₋₆alkyl (e.g. methyl), C₁₋₆haloalkyl (e.g.fluoromethyl such as trifluoromethyl), C₁₋₆alkoxy (e.g. methoxy),C₁₋₆haloalkoxy (e.g. fluoromethoxy) and halo (e.g. fluoro, e.g. chloro),examples include —CH₂-cyclopropyl and —CH₂-cyclobutyl.

When Z represents—alkylheterocyclyl wherein heterocyclyl is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl, —C(O)NHC₁₋₆alkyl C₁₋₆alkyl(e.g. methyl), —C(O)OC₁₋₆alkyl (e.g. —C(O)Omethyl), —C(O)C₁₋₆alkyl (e.g.—C(O)methyl),—C(O)NHC₁₋₆alkyl (e.g. —C(O)NHmethyl), examples include—CH₂-heterocyclyl, such as —CH₂-morpholinyl, —CH₂-piperazinyl,—CH₂-piperidinyl and —CH₂-pyrrolidinyl.

When Z represents—arylcarbocyclyl wherein carbocyclyl is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl (e.g. methyl), C₁₋₆alkoxy (e.g. methoxy), C₁₋₆haloalkyl (e.g.fluoromethyl such as trifluoromethyl), C₁₋₆haloalkoxy (e.g.fluoromethoxy) and halo (e.g. fluoro, e.g. chloro), Z may bephenylcarbocyclyl. The carbocyclyl ring may be unsubstituted or may besubstituted by one or more C₁₋₆alkyl groups. The carbocyclyl ring may bemonocyclic. An exemplary carbocyclyl ring is cycloalkyl. Examplesinclude cyclopropylphenyl- and cyclohexylphenyl-.

When Z represents—arylheterocyclyl wherein heterocyclyl is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)NHC₁₋₆alkylC₁₋₆alkyl (e.g. methyl), —C(O)OC₁₋₆alkyl (e.g. —C(O)Omethyl),—C(O)C₁₋₆alkyl (e.g. —C(O)methyl),—C(O)NHC₁₋₆alkyl (e.g. —C(O)NHmethyl),Z may be—phenylheterocyclyl. The heterocyclyl ring may be monocyclic andmay contain one or two (e.g. one) nitrogen atoms. Examples includemorphinolylphenyl-, piperazinylphenyl-, piperidinylphenyl-,pyrrolidinylphenyl-. A specific example is 3-(morpholin-4-yl)phenyl-.

Suitably R₁ represents H, methyl, ethyl, —C(O)OMe, CF₃ or OMe. In oneembodiment R₁ represents methyl.

Suitably each R₂ independently represents H or alkyl. More suitably R₂represents H or methyl. In one embodiment, R₂ represents H. In oneembodiment R₂ represents methyl.

Suitably n represents 0 or 1, for example n represents 1.

Suitably R₃ represents H or methyl, for example R₃ represents H.

Suitably R₄ represents H or methyl, for example R₄ represents H.

Suitably R₅ represents H or methyl, for example Rs represents H.

Suitably W and X are the same as each other.

Suitably W and X each represent C═O.

Suitably Y represents aryl (e.g. phenyl) or heteroaryl (e.g. 5- or6-membered monocyclic heteroaryl comprising one, two or three ringheteroatoms including one or two nitrogen atoms such as isoxazolyl,pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl). In one embodiment Yrepresents phenyl. In one embodiment Y represents monocyclic heteroaryl.In one embodiment Y is substituted by one or more substituents eachindependently selected from C₁₋₆ alkyl, C₁₋₆alkoxy, halo andC₁₋₆haloalkyl. In one embodiment Y is unsubstituted. In one embodiment Yis monosubstituted. When Y is 5-membered, suitably Z and NR₅ arepositioned on the ring at non-adjacent ring atoms. When Y is 6-membered,suitably Z and NR₅ are positioned on the ring at 1- and 4-positionsrelative to each other (i.e. Z and NR₅ have a para relationship).

Suitably Z represents aryl (e.g.phenyl) or heteroaryl (for example6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl orpyrazinyl especially pyridinyl; or 5-membered heteroaryl such asoxazolyl, thiazolyl, pyrazolyl). In one embodiment Z representsheteroaryl. In one embodiment Z represents aryl. In one embodiment, Zdoes not represent methyl or ethyl. In one embodiment Z does notrepresent unsubstituted alkyl.

In one embodiment there are provided compounds of formula (I) which arecompounds of formula (IA)

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof wherein:

R₁ represents alkyl;

each R₂ independently represents H, alkyl, carbocyclyl which may beoptionally substituted by one or more substituents each independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy and halo, —NHalkyl,—N(alkyl)₂, amino, hydroxyl, alkoxy or halo;

n represents 0, 1 or 2;

R₄ represents H or alkyl;

R₅ represents H or alkyl;

W and X each independently represent C═O or C═S (in some embodiments, Wand X are both C═O);

Y represents aryl; heteroaryl; carbocyclyl which is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo; orheterocyclyl which is optionally substituted by one or more substituentseach independently selected from C₁₋₆alkyl, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl; and

Z represents alkyl; aryl; heteroaryl; carbocyclyl which is optionallysubstituted by one or more substituents each independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy (e.g. fluoromethoxy)C₁₋₆haloalkoxy and halo; heterocyclyl which is optionally substituted byone or more substituents each independently selected from C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl; -arylcarbocyclylwherein carbocyclyl which is optionally substituted by one or moresubstituents each independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy and halo ;or -arylheterocyclyl wherein heterocyclyl whichis optionally substituted by one or more substituents each independentlyselected from C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and—C(O)NHC₁₋₆alkyl.

In one embodiment, compounds of formula (I) are provided in which R₁represents methyl; R₂ represents H; n represents 1; W and X eachrepresent C═O; R₃ represents H; R₄ represents H; Y representsisoxazolyl; and Z represents phenyl which is optionally substituted bychloro, fluoro, bromo, methyl or methoxy.

In one embodiment, compounds of formula (I) are provided in which R₁represents methyl; R₂ represents H; n represents 1; W and X eachrepresent C═O; R₃ represents H; R₄ represents H; Y represents phenyl;and Z represents phenyl which is optionally substituted by fluoro,chloro, amino, methyl or methoxy.

In one embodiment, compounds of formula (I) are provided in which R₁represents methyl; R₂ represents H; n represents 1; W and X eachrepresent C═O; R₃ represents H; R₄ represents H; Y represents pyridinyl;and Z represents pyridinyl which is optionally substituted by fluoro,chloro, methyl, amino or trifluoromethyl.

In one embodiment, compounds of formula (I) are provided in which R₁represents methyl; R₂ represents H; n represents 1; W and X eachrepresent C═O; R₃ represents H; R₄ represents H; ; Y representspyridazinyl, pyrimidinyl or pyrazinyl; and Z represents pyridinyl whichis optionally substituted by fluoro, chloro, methyl, amino ortrifluoromethyl.

In one embodiment, R₂, R₄ and R₅ are all H, n=1 and W and X are bothC═O.

In one embodiment the following compounds of formula (I) are excluded:

In one embodiment, Z is not phenyl substituted by trifluoroalkyl.

In one embodiment, when Y is isoxazolyl, Z is not positioned at the4-position of the isoxazolyl ring.

In one embodiment, the compounds of formula (I) have an IC₅₀ againstHEK293-STF3A cells of less than about 10 micromolar.

Processes

The present invention further provides a process for preparation ofcompounds of formula (I), wherein W and X each represent C═O, whichcomprises an amide coupling reaction of a compound of formula (II):

or a protected derivative thereof, wherein R₁, R₂, n, R₃, R₄, W and Xare as defined above, with a compound of formula (III)

or a protected derivative thereof, wherein R₅, Y and Z are as definedabove.

Compounds of formula (II) may be prepared by reaction of compounds offormula (IV)

wherein R₁, R₂ and n are as defined above, with a compound of formula(V)

wherein R₃ and R₄ are as defined above. An exemplary solvent for thisreaction is chloroform.

Compounds of formula (IV) can be prepared by reaction of compounds offormula (VI)

wherein R₁ is defined as above; with a compound of formula (VII)

wherein R₂ and n are as defined above and wherein LG represents aleaving group such as Br, I, tosylate etc. The reaction may take placein the presence of triethylamine or other amine base (DBU, DBN etc.) anda solvent such as 1,4-dioxane or other dipolar aprotic solvent.

Compounds of formula (III) may be synthesized by a coupling reaction,such as a Suzuki coupling reaction. When Y is isoxazole, compounds offormula (III) may alternatively be synthesized from the correspondingoxopropanenitrile by reaction with hydroxylamine hydrochloride in thepresence of sodium hydroxide. The oxopropanenitrile can be obtained fromthe corresponding ester.

The present invention further provides a process for preparation ofcompounds of formula (I), wherein W and X each represent CH₂ or aprotected derivative thereof, which comprises conversion of the W and Xgroups of compounds of formula (I) from C═O groups into CH₂ groups. Thisconversion can be carried out, for example, by reduction using boranedimethylsulfide.

The present invention further provides a process for preparation ofcompounds of formula (I), wherein W and X each represent C═S, or aprotected derivative thereof, which comprises conversion of the W and Xgroups of compounds of formula (I) from C═O groups into C═S groups. Thisconversion can be carried out, for example, by using Lawesson's reagent.

Therapeutic Uses

The present invention provides a compound of formula (I) for use as amedicament.

The compounds of the present invention may have an IC₅₀ against STF3A ofless than 20 micromolar, e.g. less than 10 micromolar. The IC₅₀ may beless than 5, 2, 1, 0.5, 0.2 or 0.1 micromolar. It may be between about0.01 and about 10 micromolar, or between about 0.01 and 5, 0.01 and 1,0.01 and 0.5, 0.01 and 0.1, 0.01 and 0.05, 0.1 and 5, 0.1 and 1, 0.1 and0.5, 0.1 and 10, 0.5 and 10, 1 and 10, 5 and 10, 1 and 5 or 0.1 and 0.5,e.g. about 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 micromolar.

The present invention provides compounds of formula (I) for use inmodulation of the WNT pathway.

The present invention also provides a method of modulating WNT activitycomprising exposing a WNT protein or a WNT receptor to a compound offormula (I).

In addition, the present invention provides use of a compound of formula(I) for modulating WNT activity.

The present invention additionally provides compounds of formula (I) foruse in the treatment of a disease or condition associated with WNTpathway activity.

A method of treating a disease or condition associated with WNT pathwayactivity comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I) is alsoprovided by the present invention.

The present invention further provides use of a compound of formula (I)for treatment of a disease or condition associated with WNT pathwayactivity.

Also provided by the present invention is use of a compound of formula(I) in the manufacture of a medicament for the treatment of a disease orcondition associated with WNT pathway activity.

The aforementioned disease or condition is suitably selected from thegroup consisting of cancer, fibrosis, stem cell and diabeticretinopathy, rheumatoid arthritis, psoriasis and myocardial infarction.

The cancer may be a cancer characterized by high WNT activity.

The disease or condition may be a cancer, such as cervical, colon,breast, bladder, head and neck, gastric, lung, ovarian, prostate,thyroid, non-small-cell lung, as well as chronic lymphocytic leukemia,mesothelioma, melanoma, pancreatic adenocarcinoma, basal cell carcinoma,osteosarcoma, hepatocellular carcinoma, Wilm's tumor or medulloblastoma,or a fibrotic disease, such as pulmonary fibrosis, liver fibrosis, skinfibrosis or renal fibrosis, or a degenerative disease, or a metabolicdisease such as diabetic retinopathy.

The present invention also provides use of a compound of formula (I) indiagnosis.

Pharmaceutical Compositions

To prepare the pharmaceutical compositions of this invention, at leastone compound of formula (I) optionally in combination with at least oneof the other aforementioned agents can be used as the activeingredient(s). The active ingredient(s) is intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration, e.g.,oral or parenteral such as intramuscular. In preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed. Thus, for liquid oral preparations, such as for example,suspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like; for solid oral preparations such as, forexample, powders, capsules, gelcaps and tablets, suitable carriers andadditives include starches, sugars, diluents, granulating agents,lubricants, binders, disintegrating agents and the like. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. If desired, tablets may be sugar coatedor enteric coated by standard techniques. For parenterals, the carrierwill usually comprise sterile water, though other ingredients, forexample, for purposes such as aiding solubility or for preservation, maybe included.

Injectable suspensions may also prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient(s) necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per dosage unit, e.g., tablet, capsule, powder, injection, suppository,teaspoonful and the like, from about 0.03 mg to 100 mg/kg (preferred0.1-30 mg/kg) and may be given at a dosage of from about 0.1-300 mg/kgper day (preferred 1-50 mg/kg per day) of each active ingredient orcombination thereof. The dosages, however, may be varied depending uponthe requirement of the patients, the severity of the condition beingtreated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofeach active ingredient or combinations thereof of the present invention.

The tablets or pills of the compositions of the present invention can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

This liquid forms in which the compositions of the present invention maybe incorporated for administration orally or by injection include,aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

The pharmaceutical composition may contain between about 0.01 mg and 100mg, preferably about 5 to 50 mg, of each compound, and may beconstituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixirs,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbetalactose, corn sweeteners, natural and synthetic gums such as acacia,tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.

The liquid forms in suitable flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compounds or combinations of the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

Compounds or combinations of the present invention may also be deliveredby the use of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamid-ephenol, or polyethyl eneoxidepolyllysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, polyacticacid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds or combinations of this invention may be administered in anyof the foregoing compositions and according to dosage regimensestablished in the art whenever treatment of the addressed disorders isrequired.

The daily dosage of the products may be varied over a wide range from0.01 to 1.000 mg per mammal per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of each active ingredient or combinationsthereof for the symptomatic adjustment of the dosage to the patient tobe treated. An effective amount of the drug is ordinarily supplied at adosage level of from about 0.1 mg/kg to about 300 mg/kg of body weightper day. Preferably, the range is from about 1 to about 50 mg/kg of bodyweight per day. The compounds or combinations may be administered on aregimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of disease condition. In addition,factors associated with the particular patient being treated, includingpatient age, weight, diet and time of administration, will result in theneed to adjust dosages.

In a further aspect, the invention also provides a process for preparinga pharmaceutical composition comprising at least one compound of formula(I), optionally in combination with at least one of the otheraforementioned agents and a pharmaceutically acceptable carrier.

The compositions are preferably in a unit dosage form in an amountappropriate for the relevant daily dosage.

Suitable dosages, including especially unit dosages, of the compounds ofthe present invention include the known dosages including unit doses forthese compounds as described or referred to in reference text such asthe British and US Pharmacopoeias, Remington's Pharmaceutical Sciences(Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, ThePharmaceutical Press) (for example see the 31st Edition page 341 andpages cited therein) or the above mentioned publications.

EXAMPLES

STF3A Cpd IC50 ID Structure IUPAC Name μM 1

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(3-methylisoxazol-5-yl)-4- oxobutanamide >10 2

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(3-phenylisoxazol-5- yl)butanamide <1 3

N-(3-(3- chlorophenyl)isoxazol-5-yl)-4- (2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 4

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-phenylisoxazol-5- yl)butanamide >10 5

N-(3-(4- chlorophenyl)isoxazol-5-yl)-4- (2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 6

N-(3-(2- chlorophenyl)isoxazol-5-yl)-4- (2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 7

N-(3-(3,4- dichlorophneyl)isoxazol-5-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 8

N-(3-(3- fluorophenyl)isoxazol-5-yl)-4- (2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 9

N-[3-(3-bromophenyl)-1,2- oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrimidin-4-yl}-4- oxobutanamide <1 10

N-[3-(3-methoxyphenyl)-1,2- oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrimidin-4-yl}-4- oxobutanamide <5 11

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-N-[3-(3-methylphenyl)- 1,2-oxazol-5-yl]-4- oxabutanamide >10 12

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(3-(o-tolyl)isoxazol-5- yl)butanamide <0.1 13

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4- yl}-4-oxo-N-{3-[3-(trifluoromethyl)phenyl]-1,2- oxazol-5-yl}butanamide >10 14

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)butanamide >10 15

N-[3-(4-aminophenyl)-1,2- oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrimidin-4-yl}-4- oxobutanamide >10 16

N-(3-(4-chloropyridin-2- yl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 17

N-(3-(5-chloropyridin-2- yl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 18

N-[3-(5-chloropyridin-3-yl)- 1,2-oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrimidin-4-yl}-4- oxobutanamide <5 19

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(3-(pyridin-3-yl)isoxazol-5- yl)butanamide >10 20

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[3-(pyridin-4-yl)- 1,2-oxazol-5-yl]butanamide >10 21

N-(3-(3-chlorophenyl)-1- methyl-1H-pyrazol-5-yl)-4-(2- methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 22

N-(3-(3-chlorophenyl)-1,2,4- oxadiazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 23

N-[5-(3-chlorophenyl)-1,2- oxazol-3-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrimidin-4-yl}-4- oxobutanamide <1 24

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(oxazol-5-yl)phenyl)-4- oxobutanamide <5 25

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(oxazol-5-yl)phenyl)-4- oxobutanamide <0.1 26

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(thiazol-2-yl)pyridin-2- yl)butanamide <0.1 27

N-(4-(1H-imidazol-1- yl)phenyl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <1 28

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)-4- oxobutanamide <0.1 29

N-(4-(1-methyl-1H-pyrazol-5- yl)phenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <1 30

N-(4-(tert-butyl)phenyl)-4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 31

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrrolidin-1- yl)phenyl)butanamide <5 32

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)-4- oxobutanamide <0.1 33

N-([1,1′-biphenyl]-4-yl)-4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 34

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-2- yl)phenyl)butanamide <0.1 35

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-3- yl)phenyl)butanamide <0.1 36

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-4- yl)phenyl)butanamide <1 37

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyridazin-3- yl)phenyl]butanamide <1 38

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrimidin-4- yl)phenyl)butanamide >10 39

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyrimidin-5- yl)phenyl]butanamide <0.1 40

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyrimidin-2- yl)phenyl]butanamide <1 41

N-([2,3′-bipyridin]-6′-yl)-4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 42

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrazin-2- yl)phenyl)butanamide <0.1 43

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridin-3- yl)butanamide <0.1 44

44Synthesis of 4-(2-methyl- 6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo- N-(5-phenylpyridin-2- yl)butanamide <0.1 45

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridazin-3- yl)butanamide <0.1 46

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4- yl}-4-oxo-N-(5-phenylpyrimidin-2- yl)butanamide <1 47

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-phenylpyrazin-2- yl)butanamide <0.1 48

N-([2,3′-bipyridin]-5-yl)-4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 49

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[5-(pyridin-3- yl)pyridin-2-yl]butanamide <0.1 50

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyrazin-2-yl)pyridin-2- yl)butanamide <0.1 51

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyridin-3-yl)pyridazin-3- yl)butanamide <0.1 52

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyridin-3-yl)pyrazin-2- yl)butanamide <0.1 53

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(3-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide >10 54

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(2-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide <0.1 55

N-(3-methoxy-[1,1′-biphenyl]- 4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 56

N-(2-methoxy-[1,1′-biphenyl]- 4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <5 57

N-(2-fluorobiphenyl-4-yl)-4- (2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 58

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(2′-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide <0.1 59

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(3′-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide <0.1 60

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4′-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide <0.1 61

N-(2′-methoxy-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 62

N-(3′-methoxy-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 63

N-(4′-methoxy-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 64

N-(2′-fluoro-[1,1′-biphenyl]-4- yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 65

N-(3′-fluoro-[1,1′-biphenyl]-4- yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 66

N-(4′-fluorobiphenyl-4-yl)-4- (2-methyl-6,7- dihydropyrazolo[1,5-a]]pyrimidin-4(5H)-yl)-4- oxobutanamide <1 67

4′-(4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxobutanamido)-[1,1′- biphenyl]-3-carboxylic acid >10 68

N,N-dimethyl-4′-(4-(2-methyl- 6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamido)-[1,1′-biphenyl]-3-carboxamide >10 69

N-(2′-amino-[1,1′-biphenyl]-4- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <1 70

N-(3′-amino-[1,1′-biphenyl]-4- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 71

N-(4′-amino-[1,1′-biphenyl]-4- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 72

N-(3′-(dimethylamino)-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 73

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(3′-morpholinobiphenyl-4-yl)-4- oxobutanamide <5 74

N-(3′-acetamido-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <5 75

N-(4-cyclohexylphenyl)-4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 76

tert-butyl 4-(4-(4-(2-methyl- 6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamido)phenyl) piperazine-1-carboxylate<0.1 77

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(piperazin-1- yl)phenyl)butanamide >10 78

N-(4-(4-acetylpiperazin-1- yl)phenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 79

Synthesis of N-ethyl-4-(6-(4- (2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamido)pyridin-3-yl)piperazine-1-carboxamide <5 80

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo- N-(4-phenylcyclohexyl)butanamide >10 81

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(1-phenylpiperidin-4- yl)butanamide >10 82

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(1-methylpiperidin-4-yl)phenyl)- 4-oxobutanamide >10 83

N-(6-(3-chlorophenyl)pyridin- 3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 84

N-(6-(3-fluorophenyl)pyridin- 3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 85

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-m-tolyl)pyridin-3- yl)butanamide <0.1 86

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-methyl-6-phenylpyridin-3-yl)- 4-oxobutanamide <5 87

N-(6-(4-fluorophenyl)pyridin- 3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <1 88

N-(6-(3- fluorophenyl)pyridazin-3-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 89

N-(5-(3-fluorophenyl)pyridin- 2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 90

N-(5-(4-fluorophenyl)pyridin- 2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 91

N-(3-methyl-5-phenylpyridin- 2-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutana <5 92

N-(4-methyl-5-phenylpyridin- 2-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <1 93

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(m-tolyl)pyridin-2- yl)butanamide <0.1 94

N-(5-fluoro-2,3′-bipyridin-6′- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 95

N-(4-fluoro-2,3′-bipyridin-6′- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 96

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-methyl-[2,3′-bipyridin]-6′-yl)- 4-oxobutanamide <0.1 97

N-(6-(3- chlorophenyl)pyridazin-3-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 98

N-(6-(3- fluorophenyl)pyridazin-3-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 99

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-4-oxo-N-(6-(m-tolyl)pyridazin-3- yl)butanamide <0.1 100

N-[6-(4- chlorophenyl)pyridazin-3-yl]- 4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4- yl}-4-oxobutanamide <0.1 101

N-(6-(4- fluorophenyl)pyridazin-3-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 102

N-(6-(5-chloropyridin-3- yl)pyridazin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 103

N-(6-(5-fluoropyridin-3- yl)pyridazin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 104

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-(5-methylpyridin-3-yl)pyridazin- 3-yl)-4-oxobutanamide <0.1 105

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(5- (trifluoromethyl)pyridin-3- yl)pyridazin-3-yl)butanamide <0.1106

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-methyl-6-(pyridin-3- yl)pyridazin-3-yl)-4- oxobutanamide <5 107

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-(6-methylpyridin-3-yl)pyridazin- 3-yl)-4-oxobutanamide <0.1 108

N-(5′-chloro-[2,3′-bipyridin]- 5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 109

N-(5′-fluoro-[2,3′-bipyridin]-5- yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 110

N-(5′-methyl-2,3′-bipyridin-5- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 111

N-(3-fluoro-2,3′-bipyridin-5- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 112

N-(5′-amino-2,3′-bipyridin-5- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <1 113

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6′-methyl-[2,3′-bipyridin]-5-yl)- 4-oxobutanamide <0.1 114

N-(5′-chloro-[3,3′-bipyridin]- 6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 115

N-(5′-fluoro-[3,3′-bipyridin]-6- yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 116

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[3,3′-bipyridin]-6-yl)- 4-oxobutanamide <0.1 117

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(piperazin-1- yl)phenyl)butanamide <0.1 118

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5′-(trifluoromethyl)-[3,3′- bipyridin]-6-yl)butanamide <0.1 119

N-(4-methyl-3,3′-bipyridin-6- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <5 120

N-(4,5′-dimethyl-3,3′- bipyridin-6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <5 121

N-(6′-methyl-3,3′-bipyridin-6- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 122

N-(5-(5-fluoropyridin-3- yl)pyrazin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 123

N-(5-(3-fluorophenyl)pyrazin- 2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 124

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(5-methylpyridin-3-yl)pyrazin-2- yl)-4-oxobutanamide <0.1 125

N-(6-methyl-5-(pyridin-3- yl)pyrazin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 126

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(m-tolyl)pyrazin-2- yl)butanamide <0.1 127

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyridin-3-yl)pyrazin-2- yl)-4-oxobutanamide <1 128

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyrazin-2-yl)pyridin-2- yl)-4-oxobutanamide <0.1 129

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrazin-2- yl)phenyl)butanamide <0.1 130

N-(3-(3- chlorophenyl)isoxazol-5-yl)- N-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 131

3-(3-chlorophenyl)-N-(4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)- yl)butyl)isoxazol-5-amine >10 132

N-(3-(3- chlorophenyl)isoxazol-5-yl)-3- methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 133

N-(3-(3- chlorophneyl)isoxazol-5-yl)-4- (6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 134

N-(3-(3- chlorophenyl)isoxazol-5-yl)-4- oxo-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)- yl)butanamide <0.1 135

N-(3-(3- chlorophenyl)isoxazol-5-yl)-4- (2-methoxy-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide >10 136

methyl 4-(4-(3-(3- chlorophenyl)isoxazol-5- ylamino)-4-oxobutanoyl)-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-2-carboxylate >10 137

N-(3-(3- chlorophenyl)isoxazol-5-yl)-4- (2-ethyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 138

N-(3-(3- chlorophenyl)isoxazol-5-yl)-4- (6-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)-4- oxobutanamide >10 139

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridazin-3- yl)butanamide <0.1 140

N-(2,3′-pyridin-5-yl)-4-(2,6- dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 141

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyridin-3-yl)pyridazin-3- yl)butanamide <0.1 142

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[3,3′-bipyridin]-6-yl)- 4-oxobutanamide <0.1 143

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-methyl-[2,3′-bipyridin]-6′-yl)- 4-oxobutanamide <0.1 144

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[2,3′-bipyridin]-5-yl)- 4-oxobutanamide <0.1 145

N-([2,3′-bipyridin]-5-yl)-2- methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 146

2-methyl-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo- N-(6-phenylpyridazin-3- yl)butanamide <0.1147

N-([3,3′-bipyridin]-6-yl)-2- methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 148

N-(4-methyl-2,3′-bipyridin-6′- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 149

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(5-methylpyrazin-2-yl)pyridin-2- yl)-4-oxobutanamide <0.1 150

2-methyl-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′- methyl-[2,3′-bipyridin]-5-yl)-4-oxobutanamide <0.1 151

2-methyl-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-(6- methylpyrazin-2-yl)pyridin-2-yl)-4-oxobutanamide <0.1 152

2-methyl-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′- methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide <0.1 153

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyrimidin-5-yl)pyridin- 2-yl)butanamide <0.1 154

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyrimidin-5-yl)pyridin- 3-yl)butanamide <1 155

N-(2-fluorobiphenyl-4-yl)-4- (2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 156

N-(5-fluoro-6-phenylpyridin- 3-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 157

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyrazin-2-yl)pyridin-2- yl)-4-oxobutanamide <0.1 158

N-(3-fluoro-5′-methyl-[2,3′- bipyridin]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 159

N-(3-(3- chlorophenyl)isoxazol-5-yl)-2- methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <5 160

(S)-4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′- methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide <0.1 161

(R)-4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′- methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide <0.1 162

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-fluoro-[2,3′-bipyridin]-5-yl)-4- oxobutanamide <0.1 163

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-fluoro-[3,3′-bipyridin]-6-yl)-4- oxobutanamide <0.1 164

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-fluoro-[2,3′-bipyridin]-6′-yl)- 4-oxobutanamide <1 165

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-fluoro-[3,3′-bipyridin]-6-yl)-4- oxobutanamide <0.1 166

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyrazin-2-yl)pyridin-3- yl)butanamide <1 167

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-(5-fluoropyridin-3-yl)pyridazin- 3-yl)-4-oxobutanamide <0.1 168

N-(3,5′-dimethyl-[2,3′- bipyridin]-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide <1 169

(S)-N-([3,3′-bipyridin]-6-yl)-4- (2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 170

(R)-N-([3,3′-bipyridin]-6-yl)-4- (2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1 171

N-([2,3′-bipyridin]-6′-yl)-4- (2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide <0.1

In one embodiment, compounds selected from Examples 1 to 171 having anIC₅₀ against STF3A cells of 10 micromolar or more are excluded.

Synthesis of the Examples

The compounds were synthesized according to the following generalsynthesis schemes:

Compounds of formula (I) in which W and X each represent C═O, and can besynthesised according to the following scheme:

Compounds of formula (I) in which W and X each represent CH₂, and can besynthesised according to the following scheme:

Compounds of formula (I) in which W and X each represent C═S, and can besynthesised according to the following scheme:

For example, compounds of formula (I) in which R₁ represents methyl, R₂represents H , n represents 1 and W and X each represent C═O, and can besynthesised according to the following scheme:

Synthesis of Amines

General Esterification Procedure

To a solution of the corresponding benzoic acid (1 equiv.) in methanol(0.65 M) was added concentrated sulphuric (32 M), and the resultingreaction mixture was heated at 70° C. for 10 h. After completion, thereaction mixture concentrated, water was added and extracted with ethylacetate. The combined organic layers were washed with aqueous sodiumbicarbonate solution and brine, dried over sodium sulphate andconcentrated under vacuum to give the desired ester.

General Formation of 3-phenyl-3-oxopropanenitrile Procedure

The corresponding ester prepared above (1 equiv.) in tetrahydrofuran(0.9 M) and acetonitrile (1 equiv.) was added dropwise to a stirredsolution of sodium hydride (1.5 equiv.) in tetrahydrofuran (0.65M). Theresulting reaction mixture was stirred at 70° C. for 16 h. Aftercompletion of starting material, the reaction mixture was quenched withice cold water and acdified to pH 5 with concentrated hydrochloric acidand extracted with ethyl acetate. The combined organic layers werewashed brine, dried over sodium sulphate and concentrated under vacuumto give the desired product.

General Formation of Amines

To a stirred solution of the corresponding 3-phenyl-3-oxopropanenitrile(1 equiv.) in water (0.7M) was added aqueous sodium hydroxide (2 equiv.)solution and hydroxylamine hydrochloride (1.1 equiv.) at roomtemperature. The resulting reaction mixture was stirred at 100° C. for 5h. After completion of starting material, the reaction mixture wascooled to room temperature and precipitated solid was collected byfiltration and dried to give the desired product.

Synthesis of 3-(2-chlorophenyl)isoxazol-5-amine Step 1: Preparation ofmethyl 2-chlorobenzoate

¹H NMR (400 MHz, DMSO-d₆): 7.84-7.82 (dd, J₁=7.6 Hz, J₂=1.2 Hz, 1H),7.47-7.40 (m, 2H), 7.34-7.26 (m, 1H), 3.94 (s, 3H). LC-MS: m/z 170.9[M+H]⁺.

Step 2: Preparation of 3-(2-chlorophenyl)-3-oxopropanenitrile

LC-MS: 178.0 [M+H]⁺.

Step 3: Preparation of 3-(2-chlorophenyl)isoxazol-5-amine

¹H NMR (400 MHz, DMSO-d₆): 7.70-7.67 (m, 1H), 7.49-7.42 (m, 1H),7.39-7.32 (m, 2H), 5.60 (s, 1H), 4.52 (brs, 2H). LC-MS: 194.9 [M+H]⁺.

Synthesis of 3-phenylisoxazol-5-amine

¹H NMR (400 MHz, DMSO-d₆): 7.73-7.74 (d, J=8.4 Hz, 2H), 7.45-7.43 (m,3H), 6.78 (brs, 2H), 5.40 (s, 1H). LC-MS: m/z 161.0 [M+H]⁺.

Synthesis of 3-(3-chlorophenyl)isoxazol-5-amine

LC-MS: m/z 195 [M+H]⁺.

Synthesis of 3-(4-chlorophenyl)isoxazol-5-amine

¹H NMR (400 MHz, DMSO-d₆): 7.76-7.74 (d, J=8.4 Hz, 2H), 7.52-7.50 (d,J=8.4 Hz, 2H), 6.85 (brs, 2H), 5.42 (s, 1H). LC-MS: m/z 194.9 [M+H]⁺.

Synthesis of 3-(3,4-dichlorophenyl)isoxazol-5-amine (VCW-WNT-168B)

¹H NMR (400 MHz, DMSO-d₆): 7.97-7.96 (m, 1H), 7.73-7.72 (m, 2H), 6.88(s, 2H), 5.51 (s, 1H). LC-MS: m/z 230 [M+H]⁺.

Synthesis of 3-(3-fluorophenyl)isoxazol-5-amine Step 1: Preparation of3-(3-fluorophenyl)-3-oxopropanenitrile

LC-MS: m/z 162.0 [M+H]⁺.

Step 2: Preparation of 3-(3-fluorophenyl)isoxazol-5-amine

¹H NMR (400 MHz, DMSO-d₆): 7.60-7.47 (m, 3H), 7.30-7.26 (t, J=8.4 Hz,1H), 6.88 (brs, 2H), 5.42 (s, 1H). LC-MS: m/z 177.0 [M+H]⁺.

Synthesis of 3-(o-tolyl)isoxazol-5-amine Step 1: Preparation of3-oxo-3-(o-tolyl)propanenitrile

¹H NMR (400 MHz, DMSO-d₆): 7.63-7.61 (m, 1H), 7.50-7.46 (m, 1H),7.34-7.31 (m, 2H), 4.03 (s, 2H), 2.57 (s, 3H).

Step 2: Preparation 3-(o-tolyl)isoxazol-5-amine

¹H NMR (400 MHz, DMSO-d₆): 7.44-7.42 (m, 1H), 7.35-7.23 (m, 3H), 6.70(s, 2H), 5.18 (s, 1H), 2.39 (s, 3H). LC-MS: m/z 175 [M+H]⁺.

Synthesis of 3-(4-chloropyridin-2-yl)isoxazol-5-amine

¹H NMR (400 MHz, Methanol-d₄): 8.55 (d, J=4.8 Hz, 1H), 7.92 (m, 1H),7.50 (dd, J=4 Hz, 2 Hz, 1H), 5.61 (s, 1H). LC-MS: m/z 196 [M+H]⁺.

Synthesis of 3-(5-chloropyridin-2-yl)isoxazol-5-amine Step 1:Preparation of 3-(5-chloropyridin-2-yl)-3-oxopropanenitrile

¹H NMR (400 MHz, DMSO-d₆): 8.81 (br s, 1H), 8.17 (br s, 1H), 8.04-8.02(m, 1H), 4.70 (br s, 2H). LC-MS: m/z 182 [M+H]⁺.

Step 2: Preparation of 3-(5-chloropyridin-2-yl)isoxazol-5-amine

¹H NMR (400 MHz, DMSO-d₆): 8.70 (m, 1H), 8.03-8.00 (m, 1H), 7.89-7.87(m, 1H), 6.88 (s, 2H), 5.44 (s, 1H). LC-MS: m/z 196 [M+H]⁺.

Synthesis of 3-(5-chloropyridin-3-yl)isoxazol-5-amine

¹H NMR (400 MHz, DMSO-d₆): 8.90 (s, 1H), 8.69 (s, 1H), 8.24 (s, 1H),6.96 (s, 2H), 5.59 (s, 1H). LC-MS: m/z 196 [M+H]⁺.

Synthesis of 3-(3-chlorophenyl)-1-methyl-1H-pyrazol-5-amine Step 1:Preparation of 3-(3-chlorophenyl)-3-oxopropanenitrile

LC-MS: m/z 178.0 [M+H]⁺.

Step 2: Preparation of 3-(3-chlorophenyl)-1-methyl-1H-pyrazol-5-amine

¹H NMR (400 MHz, DMSO-d₆): 7.81-7.77 (m, 1H), 7.72-7.70 (m, 1H),7.46-7.42 (m, 3H), 5.99 (s, 2H), 3.68 (s, 3H). LC-MS: 208 [M+H]⁺.

Synthesis of 5-(3-chlorophenyl)isoxazol-3-amine

A stirred solution of 3-(3-chlorophenyl)-3-oxopropanenitrile(1 equiv.)and hydroxylamine hydrochloride (1.2 equiv.) in a mixture of ethanol(0.02 M) and water(0.02 M) was adjusted to pH 8 using sodium hydroxidesolution and heated at 60° C. for 18 h. The reaction mixture was thenacidified to pH 2 using hydrochloride solution and further heated at 80°C. for 1 h. It was then allowed to cool to room temperature, basified topH 10, diluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over magnesium sulphate and concentrated undervacuum. The crude residue was purified by column chromatography toafford the purified product.

¹H NMR (400 MHz, DMSO-d₆): 7.83 (s, 1H), 7.74-7.71 (m, 1H), 7.52-7.51(m, 2H), 6.44 (s, 1H), 5.71 (s, 2H). LC-MS: m/z 195 [M+H]⁺.

Synthesis of 4-(pyrrolidin-1-yl)aniline Step 1: Preparation of1-(4-nitrophenyl)pyrrolidine

Triethylamine was added to a stirred solution of1-fluoro-4-nitrobenzene(1.0 equiv.) and pyrrolidine (1.3 equiv.) in2-propanol (0.1 M). The reaction was allowed to stir at reflux for 6 h.Upon consumption of starting material, solvent was evaporated todryness; the crude diluted with water; extracted with dichloromethane;organic layers combined; washed with brine; dried over magnesiumsulphate and concentrated in vacuo. The crude was dissolved inisopropanol and filtered to afford the pure product as a bright yellowsolid.

1H NMR (400 MHz, DMSO-d₆): 8.05 (d, J=9.2 Hz, 2H), 6.61 (d, J=9.2 Hz,2H), 3.39 (m, 4H), 2.00-1.97 (m, 4H). LC-MS: m/z 193 [M+H]⁺.

Step 2: Preparation of 4-(pyrrolidin-1-yl)aniline

¹H NMR (400 MHz, DMSO-d₆): 6.49 (d, J=8.4 Hz, 2H), 6.35 (d, J=8.4 Hz,2H), 4.24 (br s, 2H), 3.07 (br s, 4H), 1.90-1.87 (m, 4H). LC-MS: m/z 163[M+H]⁺.

Synthesis of 1-phenylpiperidin-4-amine

To a stirred solution of chlorobenzene (1.0 g, 8.92 mmol) in xylene (20mL) were added 4-amino piperidine (0.93 mL, 8.92 mmol), KO^(t)Bu (2.0 g,17.84 mmol), X-Phos (636 mg, 1.33 mmol) and Pd₂(dba)₃ (816 mg, 0.89mmol), degassed with argon for 10 min. The reaction mixture was heatedat 130° C. for 16 h. TLC indicated some starting material and formationof a new spot. The reaction mixture was filtered and concentrated underreduced pressure, poured into ice-cold water and extracted with EtOAc.The combined organic layer was washed with water and brine solution,dried over anhydrous sodium sulphate, filtered, concentrated underreduced pressure and purified by column chromatography to afford thedesired product.

LC-MS: m/z 175 [M+H]⁺.

Suzuki Coupling

General Suzuki Procedure A

Degas sed solution of bromoaniline derivative (1.0 equiv.) in1,4-dioxane (4 mL). Add potassium carbonate (3.0 equiv.) in water (1 mL)and boronic acid/pinacol ester to solution. Degas sed for 10 minutesbefore adding tetrakistriphenylphosphine palladium catalyst (0.1 eq).Degas for another 10 minutes and heat at reflux for 18 h. Solution isfiltered through Celite® and extracted with water and dichloromethane.The organic phase combined, dried over sodium sulphate, filtered andevaporated to dryness in vacuo. Crude was dissolved indimethylformamide, acetonitrile and water and purified with preparativeHPLC or by flash column chromatography to yield the desired product.

Synthesis of 4-(1-methyl-1H-pyrazol-5-yl)aniline

¹H NMR (400 MHz, DMSO-d₆): 7.36 (s, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.64(d, J=8.4 Hz, 2H), 6.18 (s, 1H), 5.33 (s, 2H), 3.77 (s, 3H). LC-MS: m/z174 [M+H]⁺.

Synthesis of 5-phenylpyrazin-2-amine

¹H NMR (400 MHz, DMSO-d₆): 8.49 (m, 1H), 7.96 (m, 1H), 7.92-7.90 (m,2H), 7.43-7.40 (m, 2H), 7.33-7.29 (m, 1H), 6.53 (s, 2H). LC-MS: m/z 172[M+H]⁺.

Synthesis of 3-methoxy-[1,1′-biphenyl]-4-amine

LC-MS: m/z 200 [M+H]⁺.

Synthesis of 4′-nitro-[1,1′-biphenyl]-4-amine

¹H NMR (400 MHz, Chloroform-d): 8.24 (d, J=9.2 Hz, 2H), 7.66 (d, J=9.2Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 3.87 (s, 2H).LC-MS: m/z 215 [M+H]⁺.

Synthesis of 6-(3-chlorophenyl)pyridin-3-amine Step 1: Preparation of2-(3-chlorophenyl)-5-nitropyridine

¹H NMR (400 MHz, Chloroform-d): 9.49-9.50 (m, 1H), 8.54-8.56 (m, 1H),8.11 (s, 1H), 7.95-7.97 (m, 1H), 7.89-7.91 (m, 1H), 7.48-7.51 (m, 2H).LC-MS: m/z 235 [M+H]⁺.

Step 2: Preparation of 6-(3-chlorophenyl)pyridin-3-amine

A solution of 2-(3-chlorophenyl)-5-nitropyridine in 2:1 ethanol andwater (0.1M) was added iron powder (5 equiv.) and acetic acid (5equiv.). The reaction was stirred vigorously at room temperature underambient atmosphere for 30 min. After completion of starting material,the reaction mixture was basify with 1N NaOH (pH 8-10) and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried with sodium sulphate and concentrated under vacuum to affordproduct.

¹H NMR (400 MHz, Chloroform-d): 8.17-8.18 (m, 1H), 7.89-7.90 (m, 1H),7.74-7.77 (m, 1H), 7.50-7.52 (m, 1H), 7.32-7.36 (m, 1H), 7.27-7.30 (m,1H), 7.03-7.06 (m, 1H). LC-MS: m/z 205 [M+H]⁺.

Synthesis of 6-(3-fluorophenyl)pyridin-3-amine

¹H NMR (400 MHz, DMSO-d₆): 8.14 (s, 1H), 8.02 (s, 1H), 7.76-7.74 (m,1H), 7.68-7.66 (m, 1H), 7.44-7.38 (m, 2H), 7.10-7.07 (m, 1H), 7.05-6.97(m, 1H), 5.55 (s, 2H). LC-MS: m/z 189 [M+H]⁺.

Synthesis of 6-(m-tolyl)pyridin-3-amine

¹H NMR (400 MHz, DMSO-d₆): 8.01-8.00 (m, 1H), 7.74 (bs, 1H), 7.69-7.67(m, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.09-7.07 (m,1H), 6.99-6.97 (m, 1H), 5.42 (s, 2H), 2.35 (s, 3H). LC-MS: m/z 185[M+H]⁺.

Synthesis of 5-(3-chlorophenyl)pyridin-2-amine.

LC-MS: m/z 205 [M+H]⁺.

Synthesis of 5-(3-fluorophenyl)pyridin-2-amine

¹H NMR (400 MHz, DMSO-d₆): 8.29 (s, 1H), 7.73 (dd, J=8.6 Hz, J=2.6 Hz,1H), 7.43-7.39 (m, 3H), 7.09-7.05 (m, 1H), 6.52 (d, J=8.8 Hz, 1H), 6.12(s, 2H). LC-MS: m/z 189 [M+H]⁺.

Synthesis of 5-(4-fluorophenyl)pyridin-2-amine

¹H NMR (400 MHz, Methanol-d₄): 8.20 (s, 1H), 8.09-8.10 (m, 1H),7.87-7.90 (m, 1H), 7.54-7.57 (m, 2H), 7.14-7.18 (m, 2H), 6.80-6.82 (m,1H).

Synthesis of 3-methyl-5-phenylpyridin-2-amine

¹H NMR (400 MHz, DMSO-d₆): 8.11 (s, 1H), 7.56-7.54 (m, 3H), 7.39 (t,J=7.2 Hz, 2H), 7.25 (t, J=7.6 Hz, 1H), 5.80 (s, 2H), 2.11 (s, 3H).LC-MS: m/z 185 [M+H]⁺.

Synthesis of 5-(m-tolyl)pyridin-2-amine

¹H NMR (400 MHz, DMSO-d₆): 8.22-8.21 (m, 1H), 7.68-7.66 (m, 1H),7.37-7.32 (m, 2H), 7.27 (m, 1H), 7.08-7.06 (m, 1H), 6.51 (d, J=8.8 Hz,1H), 6.01 (s, 2H), 2.34 (s, 3H). LC-MS: m/z 185 [M+H]⁺.

Synthesis of 6-(3-chlorophenyl)pyridazin-3-amine

¹H NMR (400 MHz, Methanol-d₄): 7.96 (s, 1H), 7.81-7.88 (m, 2H),7.41-7.48 (m, 2H). LC-MS: m/z 206 [M+H]⁺.

Synthesis of 6-(3-fluorophenyl)pyridazin-3-amine

¹H NMR (400 MHz, DMSO-d₆): 7.86-7.76 (m, 3H), 7.53-7.47 (m, 1H),7.23-7.18 (m, 1H), 6.85 (d, J=9.6Hz, 1H), 6.55 (s, 2H). LC-MS: m/z 190[M+H]⁺.

Synthesis of 6-(m-tolyl)pyridazin-3-amine

¹H NMR (400 MHz, DMSO-d₆): 7.79-7.77 (m, 2H), 7.74-7.72 (m, 1H), 7.34(t, J=7.6 Hz, 1H), 7.21-7.19 (m, 1H), 6.84 (d, J=9.6 Hz, 1H), 6.44 (s,2H), 2.38 (s, 3H). LC-MS: m/z 186 [M+H]⁺.

Synthesis of 6-(5-methylpyridin-3-yl)pyridazin-3-amine

¹H NMR (400 MHz, DMSO-d₆): 8.92 (d, J=2.0 Hz, 1H), 8.42 (d, J=1.6 Hz,1H), 8.15 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 6.87 (d, J=9.2 Hz, 1H), 6.56(s, 2H), 2.37 (s, 3H). LC-MS: m/z 187 [M+H]⁺.

Synthesis of 6-(6-methylpyridin-3-yl)pyridazin-3-amine

LC-MS: m/z 187[M+H]⁺.

Synthesis of 5′-fluoro-[2,3′-bipyridin]-5-amine

LC-MS: m/z 190 [M +H]⁺.

Synthesis of 6′-methyl-[2,3′-bipyridin]-5-amine

LC-MS: m/z 186 [M+H]⁺.

Synthesis of 5′-chloro-[3,3′-bipyridin]-6-amine

LC-MS: m/z 206 [M+H]⁺.

Synthesis of 5′-fluoro-[3,3′-bipyridin]-6-amine

LC-MS: m/z 190 [M+H]⁺.

Synthesis of 5-(m-tolyl)pyrazin-2-amine

¹H NMR (400 MHz, DMSO-d₆): 8.47 (d, J=1.6 Hz, 1H), 7.94 (d, J=1.6 Hz,1H), 7.73 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.12(d, J=7.2 Hz, 1H), 6.50 (s, 2H), 2.35 (s, 3H). LC-MS: m/z 186 [M +H]⁺.

General Suzuki Procedure B

To a stirred solution of the arylhalide (1 equiv.), boronic acid (1.1equiv.) and sodium carbonate (2 equiv.) in dioxane (0.02 M) and water(0.05 M) was degassed for 10 min with nitrogen.Bis(cyclopentyldiphenylphosphane) dichloromethane palladium chlorideiron (0.1 equiv.) was added to the reaction mixture and it was heated toreflux for 16 h. The reaction mixture was allowed to cool and filteredover Celite®. It was diluted with water and extracted with ethylacetate. The combined organic layers were dried with magnesium sulphateand concentrated under vacuum. The crude compound was purified by columnchromatography to afford the desired product.

Synthesis of 4-(pyridazin-3-yl)aniline

¹H NMR (400 MHz, DMSO-d₆): 9.01-9.00 (m, 1H), 7.99 (d, J=7.2 Hz, 1H),7.87 (d, J=8.8 Hz, 2H), 7.62-7.59 (m, 1H), 6.68 (d, J=8.4 Hz, 2H), 5.58(s, 2H). LC-MS: m/z 172 [M+H]⁺.

Synthesis of 4-(pyrimidin-2-yl)aniline

¹H NMR (400 MHz, DMSO-d₆): 8.72 (d, J=4.8 Hz, 2H), 8.08 (d, J=8.8 Hz,2H), 7.19 (t, J=4.8 Hz, 1H), 6.62 (d, J=8.4 Hz, 2H), 5.64 (s, 2H).LC-MS: m/z 172 [M+H]⁺.

Synthesis of 4-(pyrimidin-5-yl)aniline

¹H NMR (400 MHz, DMSO-d₆): 9.00 (m, 3H), 7.49 (d, J=8.8 Hz, 2H), 6.68(d, J=8.4 Hz, 2H), 5.45 (s, 2H). LC-MS: m/z 172 [M+H]⁺.

Synthesis of 5-phenylpyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆): 8.56 (s, 2H), 7.61 (d, J=7.2 Hz, 2H), 7.43(t, J=7.6 Hz, 2H), 7.31 (t, J=7.2 Hz, 1H), 6.75 (s, 2H). LC-MS: m/z 172[M+H]⁺.

Synthesis of [3,3′-bipyridin]-6-amine

¹H NMR (400 MHz, DMSO-d₆): 8.79 (d, J=1.6 Hz, 1H), 8.47-8.45 (m, 1H),8.29 (d, J=2.0 Hz, 1H), 7.97-7.94 (m, 1H), 7.77-7.74 (m, 1H), 7.42-7.38(m, 1H), 6.55-6.53 (m, 1H), 6.15 (s, 2H). LC-MS: m/z 172 [M+H]⁺.

Synthesis of 6-(pyridin-3-yl)pyridazin-3-amine

¹H NMR (400 MHz, DMSO-d₆): 9.14-9.13 (m, 1H), 8.60-8.59 (m, 1H),8.34-8.31 (m, 1H), 8.13 (s, 1H), 7.92 (d, J=9.6 Hz, 1H), 7.51-7.48 (m,1H), 6.92 (d, J=9.2 Hz, 1H), 6.71 (bs, 1H). LC-MS: m/z 173 [M+H]⁺.

Synthesis of 2-methyl-[1,1′-biphenyl]-4-amine

LC-MS: m/z 184 [M+H]⁺.

Synthesis of 3-methyl-[1,1′-biphenyl]-4-amine

LC-MS: m/z 184 [M+H]⁺.

Synthesis of 2′-fluoro-[1,1′-biphenyl]-4-amine

LC-MS: m/z 188 [M+H]⁺.

Synthesis of 3′-fluoro-[1,1′-biphenyl]-4-amine

1H NMR (400 MHz, DMSO-d₆): 7.41-7.32 (m, 5H), 7.02-6.99 (m, 1H), 6.63(d, J=8.4 Hz, 2H), 5.29 (s, 2H). LC-MS: m/z 188 [M+H]⁺.

Synthesis of 3′-nitro-[1,1′-biphenyl]-4-amine

¹H NMR (400 MHz, DMSO-d₆): 8.29 (t, J=2.0 Hz, 1H), 8.05-8.00 (m, 2H),7.64 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H),5.41 (s, 2H).

Synthesis of 4-(pyrazin-2-yl)aniline

MS (ESI) m/z 172 [M+H]⁺.

Synthesis of 2-fluorobiphenyl-4-amine

MS (ESI) m/z 188 [M+H]⁺.

Synthesis of 4′-fluorobiphenyl-4-amine

MS (ESI) m/z 188 [M+H]⁺.

Synthesis of 5-methyl-6-phenylpyridin-3-amine

MS (ESI) m/z 185 [M+H]⁺.

Synthesis of 4-methyl-5-phenylpyridin-2-amine

MS (ESI) m/z 186 [M+H]⁺.

Synthesis of 5-fluoro-2,3′-bipyridin-6′-amine

MS (ESI) m/z 190 [M+H]⁺.

Synthesis of 6-(4-chlorophenyl)pyridazin-3-amine

LC-MS: m/z 206 [M+H]⁺.

Synthesis of 6-(5-chloropyridin-3-yl)pyridazin-3-amine Step—1:Preparation of3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A stirred solution of 3-bromo-5-chloropyridine (1 equiv.),bis(pinacaloto) diborane (1.2 equiv.), potassium acetate (3 equiv.) in1,4-dioxane (0.2 M) was degassed with argon for 20 min. To the reactionmixture was added Pd(dppf)Cl₂.DCM (0.05 equiv.) under argon atmosphere.The reaction mixture was heated at 100° C. for 16 h. The worked-upmaterial was used in the next step without purification.

Step—2: Preparation of 6-(5-chloropyridin-3-yl)pyridazin-3-amine

LC-MS: m/z 207 [M+H]⁺.

Synthesis of 5-methyl-6-(pyridin-3-yl)pyridazin-3-amine

¹H NMR (400 MHz, DMSO-d₆): 8.71 (s, 1H), 8.60-8.59 (d, J=4.8 Hz, 1H),7.94-7.92 (d, J=7.6 Hz, 1H), 7.49-7.46 (m, 1H), 6.68 (s, 1H), 6.36 (brs,2H), 2.18 (s, 3H). LC-MS: 187.0 [M+H]⁺

Synthesis of 5′-methyl-2,3′-bipyridin-5-amine

LC-MS: m/z 186 [M+H]⁺.

Synthesis of 5′-methyl-[3,3′-bipyridin]-6-amine

¹H NMR (400 MHz, DMSO-d₆): 8.58 (s, 1H), 8.30-8.29 (m, 1H), 8.27-8.26(m, 1H), 7.78 (bs, 1H), 7.74 (dd, J=9.2 Hz, J=2.6 Hz, 1H), 6.54 (d,J=8.4 Hz, 1H), 6.12 (s, 2H), 2.33 (s, 3H). LC-MS: m/z 186 [M+H]⁺.

Synthesis of 4-methyl-3,3′-bipyridin-6-amine

LC-MS: m/z 186 [M+H]⁺.

Synthesis of 6′-methyl-3,3′-bipyridin-6-amine

MS (ESI) m/z 186 [M+H]⁺.

Synthesis of 5-(6-methylpyridin-3-yl)pyrazin-2-amine

MS (ESI) m/z 187 [M+H]⁺.

Synthesis of 4-(pyrazin-2-yl)aniline

MS (ESI) m/z 172 [M+H]⁺.

Synthesis of Di tert-butyl (6′-amino-[3,3′-bipyridin]-5-yl)carbamate

¹H NMR (400 MHz, DMSO-d₆): 8.75 (s, 1H), 8.31 (d, J=8.0 Hz, 2H), 7.94(s, 1H), 7.78 (d, J=6.8 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 6.19 (bs, 2H),1.39 (s, 18H); MS (ESI) m/z 387.30 [M+H]⁺.

Synthesis of 5-(pyridin-3-yl)pyrazin-2-amine

¹H NMR (400 MHz, DMSO-d₆): 9.11 (s, 1H), 8.58 (s, 1H), 8.51 (d, J=4.0Hz, 1H), 8.25 (d, J=11.6 Hz, 1H), 7.99 (s, 1H), 7.46-7.40 (m, 1H), 6.67(bs, 2H); MS (ESI) m/z 173.0 [M+H]⁺.

Synthesis of 4,5′-dimethyl-3,3′-bipyridin-6-amine

¹H NMR (400 MHz, DMSO-d₆): 8.35 (s, 1H), 8.31 (s, 1H), 7.73 (s, 1H),7.55 (s, 1H), 6.37 (s, 1H), 5.93 (bs, 2H), 8.31 (s, 1H), 2.33 (s, 1H),2.11 (s, 1H); MS (ESI) m/z 200.0 [M+H]⁺.

Synthesis of 5-(5-fluoropyridin-3-yl)pyrazin-2-amine Step 1: Preparationof 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A stirred solution of 3-bromo-5-fluoropyridine (1 equiv.),Bis(pinacolato) diborane (1.1 equiv.), KOAc (2 equiv.) in 1,4-dioxane(0.4 M) was degassed with argon for 20 min. To the reaction mixture,Pd(dppf)Cl₂.DCM (0.1 equiv.) was added under argon atmosphere.Thereaction mixture was heated at 110° C. for 4 h. The worked-up materialwas used in the next step without further purification.

MS (ESI) m/z 224 [M+H]⁺.

Step 2: Preparation of 5-(5-fluoropyridin-3-yl)pyrazin-2-amine

¹H NMR (400 MHz, DMSO-d₆): 9.01 (t, J=1.7 Hz, 1H), 8.65 (d, J=1.3 Hz,1H), 8.49 (d, J=3.0 Hz, 1H), 8.16-8.12 (m, 1H), 7.99 (d, J=1.3 Hz, 1H),6.79 (s, 2H); MS (ESI) m/z 191.17 [M+H]⁺.

Procedure for Acid-Intermediate:

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoicacid. Step 1: Preparation of2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

A stirred solution of 3-methyl-1H-pyrazol-5-amine (1 equiv.) in1,4-dioxane (0.5 M) was added TEA (5 equiv.) at 0° C. . After 15 minutes1,3-dibromopropane (1.2 equiv.) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 100° C. for 5 h. After completionof the reaction, the reaction mixture was filtered and washed with ethylacetate. The filtrate was concentrated under reduced pressure to affordthe intermediate.

Step 2: Preparation of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoicacid

To a stirred solution of2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1 equiv.) inchloroform (0.5 M) was added succinic anhydride (1.3 equiv.). Thereaction mixture was stirred at room temperature for 16 h. Aftercompletion, the solid which was precipitated was filtered and washedwith n-pentane and dried to afford the product.

¹H NMR (400 MHz, DMSO-d₆): 12.11 (s, 1H), 6.34 (bs, 1H), 4.02-3.99 (t,J=5.2 Hz, 2H), 3.82 (m, 2H), 2.77-2.75 (m, 2H), 2.41 (m, 2H), 2.08 (bs,5H). MS (ESI) m/z 238 [M+H]⁺.

Synthesis of4-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoic acid

To a solution of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1 equiv.)in chloroform (0.4 M) was added succinic anhydride (1.3 equiv.) at roomtemperature. The reaction mixture was stirred at room temperature for 16h. After completion, the reaction mixture was filtered and solid waswashed with chloroform and dried to afford the product.

¹H NMR (400 MHz, DMSO-d₆): 12.14 (s, 1H), 7.30 (s, 1H), 6.55 (s, 1H),4.12-4.09 (t, J=5.6 Hz, 2H), 3.88-3.86 (m, 2H), 2.80-2.77 (t, J=6.4 Hz,2H), 2.52-2.50 (m, 2H), 2.10-2.08 (m, 2H). LC-MS (ESI): MS m/z 224.0[M+H]⁺.

Synthesis of4-oxo-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)butanoicacid Step 1: Preparation of2-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

A solution of 3-(trifluoromethyl)-1H-pyrazol-5-amine (1 equiv.) in1,4-dioxane (0.2 M) was treated with 1,3-dibromopropane (1.2 equiv.) andtriethylamine (5 equiv.) at 0° C. and the reaction mixture was heated to100° C. for 12 h. After completion, reaction mixture was cooled to roomtemperature, filtered under reduced pressure and concentrated to affordcrude product. The crude product was purified by flash chromatography toafford the product.

¹H-NMR (400 MHz; DMSO-d₆): 12.25 (brs, 1H), 6.40 (s, 1H), 5.52 (s, 1H),4.03-4.00 (t, 2H), 3.58 (s, 1H), 3.18-3.15 (m, 2H), 2.05-1.97 (m, 2H).LC-MS: MS m/z 192 [M+H]⁺.

Step 2: Preparation of4-oxo-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)butanoicacid

To a solution of compound2-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1equiv.) in CHCl₃ (0.15 M) was added succinic anhydride (2 equiv.) atroom temperature. The resulted reaction mixture was stirred at roomtemperature for 60 h. After completion, the reaction mixture wasconcentrated to afford crude product. The crude product was purified bycolumn chromatography to afford the product.

¹H NMR (400 MHz, DMSO-d₆): 12.20 (s, 2H), 6.88 (s, 1H), 4.20 (t, J=6 Hz,2H), 3.92 (t, J=5.2 Hz, 2H), 2.82 (t, J=6 Hz, 2H), 2.53-2.49 (m, 3H),2.41 (s, 3H), 2.17 (brs, 2H). LC-MS: MS m/z 290 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoicacid

Step 1: Preparation of 2-methylpropane-1,3-diyl dimethanesulfonate

To a stirred solution of 2-methylpropane-1,3-diol (1 equiv.) indichloromethane (0.45 M) was added methane sulfonyl chloride (2.8equiv.), using triethylamine (2.8 equiv.) at 0° C. to room temperaturefor 16 h. Upon completion of reaction, the reaction mixture was washedwith water and brine solution, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to afford the crudeintermediate.

Step 2: Preparation of2,6-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

To a stirred solution of 2-methylpropane-1,3-diyl dimethanesulfonate(1.2 equiv.) in 1,4-dioxane (0.5 M) were added3-methyl-1H-pyrazol-5-amine (1 equiv.) and triethylamine (5 equiv.). Thereaction mixture was heated at 100° C. for 48 h. Upon completion, thereaction mixture was filtered and concentrated under reduced pressure,purified by column chromatography to afford the intermediate.

Step 3: Preparation of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoicacid

To a stirred solution of2,6-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1 equiv.) inchloroform (0.15 M) was added succinic anhydride (1 equiv.) and thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was concentrated under reduced pressure to afford the product.

¹H NMR (400 MHz, DMSO-d₆): 12.08 (s, 1H), 6.35 (brs, 1H), 4.12-4.08 (m,1H), 3.99 (brs, 1H), 3.64-3.58 (m, 1H), 3.35 (brs, 1H), 2.85-2.79 (m,1H), 2.74-2.70 (brs, 1H), 2.49-2.48 (m, 2H), 2.25 (brs, 1H), 2.08 (brs,3H), 1.04-1.02 (d, J=6.1 Hz, 3H). MS (ESI) m/z 252.07 [M+H]⁺.

Synthesis of ethyl2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoate

Step 1: Preparation of2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

To a stirred solution of 3-methyl-1H-pyrazol-5-amine (1 equiv.) in1,4-dioxane (0.1 M) was added triethylamine (5 equiv.) at 0° C. After 15minutes, 1,3-dibromopropane (1.2 equiv.) was added to the reactionmixture at 0° C. The reaction mixture was stirred at 100° C. for 5 h.The reaction mixture was filtered and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure to afford theintermediate.

Step 2: Preparation of2-bromo-1-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone

To a stirred solution of2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1 equiv.) indichloromthane (0.6 M) was added 2-bromoacetyl bromide (2 equiv.) dropwise at 0° C. The reaction mixture was stirred at room temperature for12 h. The solid thus formed was filtered and washed with n-pentane thendried to afford the intermediate.

Step 3: Preparation of ethyl2-(diethoxyphosphoryl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoate

To a stirred solution of NaH (60% suspension in mineral oil) (1.2equiv.) in DMSO (0.5 M) was added ethyl 2-(diethoxyphosphoryl)acetate(1.1 equiv.) at room temperature. After 30 min, to the reaction mixturewas added2-bromo-1-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone(1 equiv.) portion-wise at room temperature. The reaction mixture wasstirred at 70° C. for 4 h. The reaction mixture was quenched withice-cold water and extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulphate and concentrated under reducedpressure to obtain the crude product. The crude product was purified bycolumn chromatography to afford the intermediate. LC-MS: m/z 402 [M+H]⁺.

Step 4: Preparation of ethyl4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-2-methylene-4-oxobutanoate

To a stirred solution of ethyl2-(diethoxyphosphoryl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoate(1 equiv.) in THF (0.4 M) was added aqueous K₂CO₃ (1.5 equiv., 2 M)followed by aq. HCHO (20 equiv.) at room temperature. The reactionmixture was stirred at 80° C. for 45 min. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulphate and concentrated under reducedpressure to obtain the crude product. The crude product was purified bycolumn chromatography to afford the product. LC-MS: m/z 278 [M+H]⁺.

Step 5: Preparation of ethyl2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoate

To a solution of ethyl4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-2-methylene-4-oxobutanoate(1 equiv.) in ethanol (0.1 M) was added a slurry of 10% Pd/C (10% w/w)in methanol under nitrogen and the reaction mixture was hydrogenatedunder H₂ (50 psi) at room temperature for 8 h. The reaction mixture wasfiltered through celite bed and washed with methanol. The filtrate wasconcentrated under reduced pressure to give crude product. The crudeproduct was purified by column chromatography to afford the product. ¹HNMR (400 MHz, DMSO-d₆): 6.33 (brs, 1H), 4.08-4.03 (m, 4H), 3.99-3.81 (m,2H), 2.93-2.79 (m, 2H), 2.72-2.67 (m, 1H), 2.08 (brs, 5H), 1.19-1.13 (m,6H). MS (ESI) m/z 280 [M+H]⁺.

General Procedure for Amide Coupling Reactions:

Amide Coupling Method A:

A solution of the respective amine (1 equiv.) and acid-intermediate (1.1equiv.) in pyridine (0.1 M) was cooled to 0° C. under nitrogenatmosphere and treated with POCl₃ (3 equiv.). The reaction mixturestirred for 45 min. After consumption of starting material, the reactionmixture was quenched with saturated sodium bicarbonate and extractedwith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated under vacuum. The crude compound was purified byreversed phase chromatography to afford desired product.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(3-methylisoxazol-5-yl)-4-oxobutanamide,Compound 1

¹H NMR (400 MHz, Methanol-d₄): 6.15 (s, 1H), 4.55 (s, 1H), 4.10 (t,J=6.0 Hz, 2H), 3.91-3.94 (m, 2H), 2.96-2.98 (m, 2H), 2.78 (t, J=6.0 Hz,2H), 2.22 (bs, 2H), 2.17 (s, 3H). LC-MS: m/z 318 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(3-phenylisoxazol-5-yl)butanamide,Compound 2

¹H NMR (400 MHz, DMSO-d₆): 11.80 (s, 1H), 7.84-7.83 (d, J=2.8 Hz, 2H),7.50-7.48 (m, 3H), 6.68 (s, 1H), 6.34 (s, 1H), 4.07 (m, 2H), 3.86 (m,2H), 2.92-2.90 (m, 2H), 2.73-2.71 (t, J=5.2 Hz, 2H), 2.07-2.05 (m, 5H).LC-MS: 380.2 [M+H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 3

¹H NMR (400 MHz, Methanol-d₄): 7.66 (s, 1H), 7.60-7.58 (m, 1H),7.33-7.29 (m, 2H), 6.53 (s, 1H), 6.13 (brs, 1H), 3.81 (brs, 2H), 3.64(s, 1H), 2.70 (brs, 2H), 2.52-2.51 (m, 2H), 2.29 (s, 2H), 1.86 (brs,5H). LC-MS: MS m/z 414 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-phenylisoxazol-5-yl)butanamide,Compound 4

¹H NMR (400 MHz, DMSO-d₆): 8.99 (s, 1H), 7.58-7.57 (d, J=7.2 Hz, 1H),7.38-7.34 (t, J=7.2 Hz, 2H), 7.29-7.25 (t, J=7.2 Hz, 1H), 6.68 (brs,1H), 6.35 (brs, 1H), 4.00-3.97 (t, J=6.0 Hz, 2H), 3.83-3.80 (t, J=6.0Hz, 2H), 2.67-2.64 (m, 2H), 2.07 (brs, 5H). LC-MS: MS m/z 380 [M+H]⁺.

Synthesis ofN-(3-(4-chlorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 5

¹H NMR (400 MHz, DMSO-d₆): 11.83 (s, 1H), 7.88-7.86 (d, J=8 Hz, 2H),7.57-7.55 (d, J=8.8 Hz, 2H), 6.71 (s, 1H), 6.33 (s, 1H), 4.02-4.01 (t,J=5.2 Hz, 2H), 3.87-3.85 (m, 2H), 2.92-2.89 (m, 2H), 2.73-2.70 (t, J=6.4Hz, 2H), 2.05-2.03 (m, 5H). LC-MS: 414.2 [M+H]⁺

Synthesis ofN-(3-(2-chlorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 6

¹H NMR (400 MHz, DMSO-d₆): 11.89 (s, 1H), 7.69-7.67 (d, J=7.2 Hz, 1H),7.64-7.62 (d, J=8.4 Hz, 1H), 7.55-7.53 (t, J=7.6 Hz, 1H), 7.49-7.45 (t,J=7.2 Hz, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 4.03-3.99 (m, 2H), 3.86-3.83(m, 2H), 2.93-2.90 (m, 2H), 2.72-2.70 (t, J=6 Hz, 2H), 2.08-2.05 (m,5H). LC-MS: 414.15 [M+H]⁺.

Synthesis ofN-(3-(3,4-dichlorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 7

¹H NMR (400 MHz, DMSO-d₆): 11.84 (br s, 1H), 8.10 (d, J=2 Hz, 1H),7.86-7.83 (m, 1H), 7.76 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 4.02 (t, J=6.0Hz, 2H), 3.86 (br s, 2H), 2.91-2.89 (m, 2H), 2.71-2.67 (m, 2H), 2.08 (brs, 5H). LC-MS: m/z 449 [M+H]⁺.

Synthesis ofN-(3-(3-fluorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 8

¹H NMR (400 MHz, DMSO-d₆): 11.84 (s, 1H), 7.71-7.67 (t, J=7.2 Hz, 2H),7.57-7.52 (q, J=8.4 Hz 1H), 7.37-7.32 (m, 1H), 6.76(s, 1H), 6.34 (s,1H), 4.03-4.01 (m, 2H), 3.88-2.85 (m, 2H), 2.92-2.90 (m, 2H), 2.73-2.70(t, J=5.6 Hz, 2H), 2.09-2.05 (m, 5H).LC-MS: 398.2 [M+H]⁺.

Synthesis ofN-[3-(3-bromophenyl)-1,2-oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxobutanamide,Compound 9

¹H NMR (400 MHz, Methanol-d₄) 7.97 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.62(d, J=8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.44 (br s,1H), 4.10 (t, J=6.0 Hz, 2H), 3.94 (br s, 2H), 3.00 (br s, 2H), 2.82 (t,J=6.8 Hz, 2H), 2.22-2.17 (m, 5H). LC-MS: m/z 459 [M+H]⁺.

Synthesis ofN-[3-(3-methoxyphenyl)-1,2-oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxobutanamide,Compound 10

¹H NMR (400 MHz, Methanol-d₄) 7.40-7.33 (m, 3H), 7.04-7.01 (m, 1H), 6.65(s, 1H), 6.45 (br s, 1H), 4.10 (t, J=6.0 Hz, 2H), 3.95 (t, J=5.6 Hz,2H), 3.84 (s, 3H), 3.00 (br s, 2H), 2.82 (t, J=6.8 Hz, 2H), 2.22-2.17(m, 5H). LC-MS: m/z 410 [M+H]⁺.

Synthesis of4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-N-[3-(3-methylphenyl)-1,2-oxazol-5-yl]-4-oxobutanamide,Compound 11

¹H NMR (400 MHz, Methanol-d₄) 7.61-7.56 (m, 2H), 7.36-7.27 (m, 2H), 6.64(s, 1H), 6.46 (br s, 1H) , 4.10 (t, J=Hz, 2H), 3.95-3.93 (m, 2H), 3.00(s, 2H), 2.82 (t, J=6.4Hz, 2H), 2.39 (s, 3H), 2.22-2.17 (m, 5H). LC-MS:m/z 394 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(3-(o-tolyl)isoxazol-5-yl)butanamide,Compound 12

¹H NMR (400 MHz, DMSO-d₆) 11.79 (br s, 1H), 7.50-7.49 (m, 1H), 7.40-7.28(m, 3H), 6.45 (s, 1H), 6.33 (br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.85 (s,2H), 2.91-2.90 (m, 2H), 2.73-2.70 (m, 2H), 2.41 (s, 3H), 2.08 (s, 5H).LC-MS: m/z 394 [M+H]⁺.

Synthesis of4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-{3-[3-(trifluoromethyl)phenyl]-1,2-oxazol-5-yl}butanamide,Compound 13

¹H NMR (400 MHz, Chloroform-d) 9.34-9.25 (m, 1H), 8.05 (s, 1H), 7.97 (d,J=7.6Hz, 1H), 7.68 (d, J=7.6Hz, 1H)) , 7.56 (t, J=8.0Hz, 1H), 6.71 (s,1H), 4.17 (t, J=6.4Hz, 2H), 3.99-3.88 (m, 2H), 3.09-2.98 (m, 2H),2.88-2.86 (m, 2H), 2.24-2.19 (m, 5H). LC-MS: m/z 448 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butanamide,Compound 14

¹H NMR (400 MHz, Methanol-d₄) 7.78-7.80 (m, 2H), 7.68-7.72 (m, 4H),7.63-7.65 (m, 2H), 4.55 (s, 1H), 4.10 (t, J=6.0 Hz, 2H), 3.94-3.96 (m,2H), 2.98-3.00 (m, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.22 (bs, 2H), 2.18 (s,3H). LC-MS: m/z 457 [M+H]⁺.

Synthesis ofN-[3-(4-aminophenyl)-1,2-oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxobutanamide,Compound 15 Step 1: Preparation of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-(4-nitrophenyl)isoxazol-3-yl)-4-oxobutanamide

¹H NMR (400 MHz, DMSO-d₆) 11.90 (s, 1H), 8.33 (d, J=8.8 Hz, 2H), 8.14(d, J=8.8 Hz, 2H),6.85 (s, 1H), 6.34 (br s, 1H), 4.02 (t, J=5.6 Hz, 2H),3.86 (s, 2H), 2.92 (s, 2H), 2.73 (t, J=6.4 Hz, 2H), 2.08 (s, 5H). LC-MS:m/z 425 [M+H]⁺.

Step 2: Preparation ofN-[3-(4-aminophenyl)-1,2-oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxobutanamide

4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-N-[3-(4-nitrophenyl)-1,2-oxazol-5-yl]-4-oxobutanamide(1 equiv.), ammonium chloride (4 equiv.), and iron (2 equiv.) were addedto a solution of ethanol (0.02 M) and water (0.08 M), and heated at 40°C. for 3h. The reaction mixture was then filtered, diluted with waterand extracted with ethyl acetate. The combined organic layers were driedover MgSO₄ and concentrated under vacuum. The crude product was purifiedby reversed phase preparative HPLC to afford the purified product.

¹H NMR (400 MHz, DMSO-d₆) 11.61 (br s, 1H), 7.46 (d, J=8.8 Hz, 2H),6.61(d, J=8.8 Hz, 2H), 6.46 (s, 1H), 6.34 (br s, 1H), 5.50 (s, 2H), 4.02(t, J=5.6 Hz, 2H), 3.85 (s, 2H), 2.90 (s, 2H), 2.69 (t, J=6.4 Hz, 2H),2.08 (s, 5H). LC-MS: m/z 395 [M+H]⁺.

Synthesis ofN-(3-(4-chloropyridin-2-yl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 16

¹H NMR (400 MHz, DMSO-d₆): 11.90 (br s, 1H), 8.69 (d, J=5.6 Hz, 1H),8.03 (d, J=1.6 Hz, 1H), 7.67 (dd, J=4.0 Hz, 2 Hz, 1H), 6.71 (s, 1H),6.33 (br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.86 (br s, 2H), 2.93-2.89 (m,2H), 2.72-2.70 (m, 2H), 2.08 (br s, 5H). LC-MS: m/z 415 [M+H]⁺.

Synthesis ofN-(3-(5-chloropyridin-2-yl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 17

¹H NMR (400 MHz, DMSO-d₆): 11.88 (br s, 1H), 8.76 (d, J=2 Hz, 1H),8.09-8.07 (m, 1H), 8.01-7.99 (m, 1H), 6.68 (s, 1H), 6.33 (br s, 1H),4.02 (t, J=5.8 Hz, 2H), 3.86 (br s, 2H), 2.91 (t, J=6 Hz, 2H), 2.70 (t,J=6.2 Hz, 2H), 2.08 (br s, 5H). LC-MS: m/z 415 [M+H]⁺.

Synthesis ofN-[3-(5-chloropyridin-3-yl)-1,2-oxazol-5-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxobutanamide,Compound 18

¹H NMR (400 MHz, DMSO-d₆) 11.83 (br s, 1H), 9.01 (d, J=1.6 Hz, 1H), 8.75(d, J=2.4 Hz, 1H), 4.05 (t, J=2.0 Hz, 1H), 6.90 (s, 1H), 6.33 (br s,1H), 4.03 (t, J=6.0 Hz, 2H), 3.86 (s, 2H), 2.92-2.91 (m, 2H), 2.74-2.71(m, 2H), 2.08 (s, 5H). LC-MS: m/z 415 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(3-(pyridin-3-yl)isoxazol-5-yl)butanamide,Compound 19

¹H NMR (400 MHz, DMSO-d₆): 11.85 (br s, 1H), 9.03 (s, 1H), 8.69-8.67 (m,1H), 8.23 (d, J=8.0 Hz, 1H), 7.55-7.51 (m, 1H), 6.78 (s, 1H), 6.33 (brs, 1H), 4.02 (t, J=5.8 Hz, 2H), 3.86 (br s, 2H), 2.91-2.90 (m, 2H), 2.71(t, J=6.0 Hz, 2H), 2.08 (br s, 5H). LC-MS: m/z 381 [M+H]⁺.

Synthesis of4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[3-(pyridin-4-yl)-1,2-oxazol-5-yl]butanamide,Compound 20

¹H NMR (400 MHz, Methanol-d₄): 8.66 (d, J=6.4 Hz, 2H), 8.09 (s, 1H),7.84 (d, J=6.4 Hz, 2H), 6.79 (s, 1H), 6.44 (br s, 1H), 4.10 (t, J=7.6Hz, 2H), 3.95-3.93 (m, 2H), 3.01 (s, 2H), 2.84-2.81 (m, 2H), 2.21-2.17(m, 5H). LC-MS: m/z 381 [M+H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 21

¹H NMR (400 MHz, DMSO-d₆): 10.13 (s, 1H), 7.79 (s, 1H), 7.72-7.70 (d,J=8 Hz, 1H), 7.43-7.39 (t, J=8 Hz, 1H), 7.34-7.32 (d, J=8.8 Hz, 1H),6.70 (s, 1H), 6.36 (s, 1H), 4.02-4.00 (t, J=5.6 Hz, 2H), 3.88-3.85 (m,2H), 3.72 (s, 3H), 2.92-288 (m, 2H), 2.70-2.67 (t, J=6.4 Hz, 2H),2.09-2.07 (m, 5H). LC-MS: 427.1 [M+H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 22

¹H NMR (400 MHz, Chloroform-d): 8.05 (1H, t), 7.93-7.95 (1H, m),7.46-7.52 (1H, m), 7.40 (1H, t), 4.17 (2H, t), 3.66 (2H, bs), 3.07(4H,m), 2.18(5H, m). LC-MS: m/z 415.1 [M+H]⁺.

Synthesis ofN-[5-(3-chlorophenyl)-1,2-oxazol-3-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxobutanamide,Compound 23

¹H NMR (400 MHz, DMSO-d₆): 11.14 (s, 1H), 7.97 (s, 1H), 7.86-7.84 (m,1H), 7.57-7.56 (m, 2H), 7.45 (s, 1H), 6.33 (br s, 1H), 4.03 (t, J=6.0Hz, 2H), 3.86 (s, 2H), 2.91-2.88 (m, 2H), 2.72-2.69 (m, 2H), 2.09 (s,5H). LC-MS: m/z 414 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4-(oxazol-5-yl)phenyl)-4-oxobutanamide,Compound 24

¹H NMR (400 MHz, DMSO-d₆): 10.18 (s, 1H), 8.38 (s, 1H), 7.71-7.64 (m,5H), 7.56 (s, 1H), 6.34 (bs, 1H), 4.04-4.01 (t, J=6 Hz, 2H), 3.86 (bs,2H), 2.88-2.87 (m, 2H), 2.67-2.64 (m, 2H), 2.08 (bs, 5H). LC-MS: m/z 380[M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4-(oxazol-5-yl)phenyl)-4-oxobutanamide,Compound 25

¹H NMR (400 MHz, DMSO-d₆): 10.25 (s, 1H), 7.90-7.86 (m, 3H), 7.73-7.70(m, 3H), 4.04-4.01 (m, 2H), 3.86 (br s, 2H), 2.90-2.87 (m, 2H),2.69-2.66 (m, 2H), 2.08 (br s, 5H). LC-MS: m/z 396 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(thiazol-2-yl)pyridin-2-yl)butanamide,Compound 26

¹H NMR (400 MHz, DMSO-d₆): 8.87 (s, 1H), 8.49 (br s, 1H), 8.28-8.21 (m,2H), 7.88 (d, J=3.2 Hz, 1H), 7.34 (d, J=3.2 Hz, 1H), 6.55 (br s, 0.5H),5.81 (br s, 0.5H), 4.16 (t, J=6.2 Hz, 2H), 3.93 (br s, 2H), 3.05-2.96(m, 2H), 2.86-2.84 (m, 2H), 2.23-2.18 (m, 5H). LC-MS: m/z 397 [M+H]⁺.

Synthesis ofN-(4-(1H-imidazol-1-yl)phenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 27

¹H NMR (400 MHz, DMSO-d₆): 10.17 (s, 1H), 8.17 (br s, 1H), 7.72-7.68 (m,3H), 7.57-7.55 (m, 2H), 7.09 (br s, 1H), 6.34 (br s, 1H), 4.02 (t, J=6.0Hz, 2H), 3.86 (br s, 2H), 2.88 (t, J=6.4 Hz, 2H), 2.65 (t, J=6.4 Hz,2H), 2.08 (br s, 5H). LC-MS: m/z 379 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)-4-oxobutanamide,Compound 28

¹H NMR (400 MHz, DMSO-d₆): 10.08 (s, 1H), 7.85 (d, J=8.4 Hz, 2H),7.78)s, 1H), 7.64 (d, J=8.8 Hz, 2H), 6.31 (bs, 1H), 4.02 (t, J=6.0 Hz,2H), 3.86 (bs, 2H), 2.88 (t, J=6.2 Hz, 2H), 2.70 (s, 3H), 2.67-2.64 (m,2H), 2.08 (bs, 5H). LC-MS: m/z 410 [M+H]⁺.

Synthesis ofN-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 29

¹H NMR (400 MHz, DMSO-d₆): 10.17 (s, 1H), 7.71 (d, J=8.4 Hz, 2H),7.46-7.43 (m, 3H), 6.34 (d, J=2 Hz, 2H), 4.02 (t, J=6 Hz, 2H), 3.87 (brs, 2H), 3.83 (s, 3H), 2.89 (t, J=6.2 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H),2.08 (br s, 5H). LC-MS: m/z 393 [M+H]⁺.

Synthesis ofN-(4-(tert-butyl)phenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 30

¹H NMR (400 MHz, DMSO-d₆): 9.90 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.29(d, J=8.8 Hz, 2H), 6.34 (br s, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.85 (br s,2H), 2.87-2.84 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.07 (br s, 5H), 1.25(s, 9H). LC-MS: m/z 369 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrrolidin-1-yl)phenyl)butanamide,Compound 31

¹H NMR (400 MHz, Methanol-d₄): 7.30 (d, J=8.8 Hz, 2H), 6.53 (d, J=8.8Hz, 2H), 4.10 (t, J=6.2 Hz, 2H), 3.93 (t, J=5.6 Hz, 2H), 3.26-3.23 (m,4H), 2.95 (bs, 2H), 2.72 (t, J=6.6 Hz, 2H), 2.33-2.18 (m, 6H), 2.02-2.00(m, 4H). LC-MS: m/z 382 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)-4-oxobutanamide,Compound 32

¹H NMR (400 MHz, DMSO-d₆) 10.65 (s, 1H), 8.87 (s, 1H), 8.26-8.24 (m,1H), 8.12-8.10 (m, 1H), 7.96 (s, 1H), 6.33 (br s, 1H), 4.02 (t, J=6.0Hz, 2H), 3.85 (s, 2H), 2.89-2.86 (m, 2H), 2.74-2.72 (m, 5H), 2.07 (s,5H). LC-MS: m/z 411 [M+H]⁺.

Synthesis ofN-([1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 33

¹H NMR (400 MHz, DMSO-d₆): 10.09 (s, 1H), 7.70-7.68 (m, 2H), 7.64-7.60(m, 4H), 7.43 (m, 2H), 7.33-7.31 (m, 1H), 6.35 (bs, 1H), 4.02 (t, J=6Hz, 2H), 3.87 (bs, 2H), 2.89 (t, J=6.4 Hz, 2H), 2.68-2.65 (m, 2H), 2.08(bs, 5H). LC-MS: m/z 389 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-2-yl)phenyl)butanamide,Compound 34

¹H NMR (400 MHz, DMSO-d₆): 10.15 (s, 1H), 8.62 (d, J=4.4 Hz, 1H), 8.04(d, J=8.4 Hz, 2H), 7.91-7.89 (m, 1H), 7.86-7.82 (m, 1H), 7.71 (d, J=8.4Hz, 2H), 7.31-7.27 (m, 1H), 6.34 (br s, 1H), 4.03 (t, J=5.8 Hz, 2H),3.87 (br s, 2H), 2.91-2.88 (m, 2H), 2.69-2.66 (m, 2H), 2.08 (br s, 5H).LC-MS: m/z 390 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-3-yl)phenyl)butanamide,Compound 35

¹H NMR (400 MHz, DMSO-d₆): 10.14 (s, 1H), 8.87 (s, 1H), 8.52 (s, 1H),8.04 (d, J=8.0 Hz, 1H), 7.70 (q, J=9.2 Hz, 4H) 7.47-7.44 (m, 1H), 6.35(br s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (br s, 2H), 2.89 (t, J=6.2 Hz,2H), 2.67 (t, J=6.2 Hz, 2H), 2.08 (br s, 5H). LC-MS: m/z 390 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-4-yl)phenyl)butanamide,Compound 36

¹H NMR (400 MHz, DMSO-d₆): 10.20 (s, 1H), 8.59 (d, J=5.4 Hz, 2H), 7.76(q, J=8.8 Hz, 4H), 7.68 (d, J=6 Hz, 2H), 6.34 (br s, 1H), 4.10-4.01 (t,J=6.0 Hz, 2H), 3.86 (br s, 2H), 2.91-2.88 (t, J=6.2 Hz, 2H), 2.67 (t,J=6.2 Hz, 2H), 2.08 (br s, 5H). LC-MS: m/z 390 [M+H]⁺.

Synthesis of4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyridazin-3-yl)phenyl]butanamide,Compound 37

¹H NMR (400 MHz, DMSO-d₆): 10.24 (s, 1H), 8.18-8.11 (m, 3H), 7.79-7.73(m, 3H), 6.35 (br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.87 (s, 2H),2.90-2.88 (m, 2H), 2.69 (t, J=6.4 Hz, 2H), 2.08 (s, 5H). LC-MS: m/z 391[M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrimidin-4-yl)phenyl)butanamide,Compound 38

¹H NMR (400 MHz, DMSO-d₆): 10.29 (s, 1H), 9.17 (d, J=1.2 Hz, 1H), 8.79(d, J=5.2 Hz, 1H), 8.19-8.17 (m, 2H), 8.03-8.01 (m, 1H), 7.78-7.76 (m,2H), 6.33 (br s, 1H), 4.02 (t, J=5.6 Hz, 2H), 3.86 (s, 2H), 2.91-2.88(m, 2H), 2.70-2.67 (m, 2H), 2.39 (s, 3H), 2.08 (s, 5H). LC-MS: m/z 391[M+H]⁺.

Synthesis of4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyrimidin-5-yl)phenyl]butanamide,Compound 39

¹H NMR (400 MHz, DMSO-d₆): 10.20 (s, 1H), 9.13-9.11 (m, 3H), 7.79-7.74(m, 4H), 6.34 (br s, 1H), 4.04-4.01 (m, 2H), 3.86 (s, 2H), 2.89 (t,J=6.4 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 2.08 (br s, 5H). LC-MS: m/z 391[M+H]⁺.

Synthesis of4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyrimidin-2-yl)phenyl]butanamide,Compound 40

¹H NMR (400 MHz, Methanol-d₄): 8.82 (d, J=4.8 Hz, 2H), 8.36 (d, J=8.8Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 7.32 (t, J=4.8 Hz, 1H), 4.12 (t, J=6.0Hz, 2H), 3.98-3.96 (m, 2H), 3.01 (br s, 2H), 2.82 (t, J=6.8 Hz, 2H),2.24-2.20 (m, 5H). LC-MS: m/z 391 [M+H]⁺.

Synthesis ofN-([2,3′-bipyridin]-6′-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 41

¹H NMR (400 MHz, Chloroform-d): 10.72 (1H, s), 9.02 (1H, d, J=2.0 Hz),8.66 (1H, d, J=4.4 Hz), 8.43 (1H, dd, J=8.4, 2.4 Hz), 8.17 (1H, d, J=8.8Hz), 8.00 (1H, d, J=8.0 Hz), 7.86-7.91 (1H, m), 7.35-7.38 (1H, m), 6.34(1H, bs), 4.02 (2H, t), 3.86 (2H, bs), 2.89(2H, t), 2.74 (2H, t),2.08(5H, m). LC-MS: m/z 391.1 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrazin-2-yl)phenyl)butanamide,Compound 42

¹H NMR (400 MHz, DMSO-d₆): 10.24 (s, 1H), 9.21 (d, J=1.6 Hz, 1H),8.68-8.65 (m, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.12-8.08 (m, 2H), 7.80-7.72(m, 2H), 6.35 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (bs, 2H), 2.95-2.85(m, 2H), 2.72-2.65 (m, 2H), 2.08 (bs, 5H). MS (ESI) m/z 391 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridin-3-yl)butanamide,Compound 43

¹H NMR (400 MHz, Chloroform-d): 8.66 (1H, s), 8.52 (1H, bs), 8.23 (1H,bs), 8.10 (1H, s), 7.89 (2H, d, J=7.6 Hz), 7.65 (1H, d, J=8.8 Hz),7.37-7.47 (3H, m), 4.17 (2H, t), 3.90 (2H, bs), 2.98 (2H, m), 2.82 (2H,t), 2.23 (5H, m). LC-MS: m/z 390.1 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-phenylpyridin-2-yl)butanamide,Compound 44

¹H NMR (400 MHz, Chloroform-d): 8.66 (1H, s), 8.52 (1H, bs), 8.23 (1H,bs), 8.10 (1H, s), 7.89 (2H, d, J=7.6 Hz), 7.65 (1H, d, J=8.8 Hz),7.37-7.47 (3H, m), 4.17 (2H, t), 3.90 (2H, bs), 2.98 (2H, m), 2.82 (2H,t), 2.23 (5H, m). LC-MS: m/z 390.1 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridazin-3-yl)butanamide,Compound 45

¹H NMR (400 MHz, DMSO-d₆): 11.25 (1H, s), 8.36 (1H, d, J=9.6 Hz), 8.21(1H, d, J=9.6 Hz), 8.09 (2H, d, J=7.2 Hz), 7.49-7.56 (3H, m), 6.33 (1H,bs), 4.02 (2H, t), 3.86 (2H, bs), 2.91(2H, t), 2.80 (2H, t), 2.08(5H,m). LC-MS: m/z 391.1 [M+H]⁺.

Synthesis of4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-(5-phenylpyrimidin-2-yl)butanamide,Compound 46

¹H NMR (400 MHz, DMSO-d₆): 10.71 (s, 1H), 8.98 (s, 2H), 7.77 (d, J=7.2Hz, 2H), 7.51 (t, J=7,2 Hz, 2H), 7.43 (t, J=7.2 Hz, 1H), 6.34 (br s,1H), 4.02 (t, J=6.0 Hz, 2H), 3.86 (s, 2H), 2.90-2.87 (s, 4H), 2.08 (s,5H). LC-MS: m/z 391 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-phenylpyrazin-2-yl)butanamide,Compound 47

¹H NMR (400 MHz, DMSO-d₆): 10.93 (s, 1H), 9.37 (s, 1H), 9.00 (s, 1H),8.10-8.08 (m, 2H), 7.53-7.45 (m, 3H), 6.34 (bs, 1H), 4.03 (t, J=6.0 Hz,2H), 3.87 (bs, 2H), 2.93-2.90 (m, 2H), 2.79-2.76 (m, 2H), 2.08 (bs, 5H).LC-MS: m/z 391 [M+H]⁺.

Synthesis ofN-([2,3′-bipyridin]-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 48

¹H NMR (400 MHz, DMSO-d₆): 10.50 (s, 1H), 9.21 (s, 1H), 8.89 (d, J=2.0Hz, 1H), 8.58 (dd, J=4 Hz, 1.2 Hz, 1H), 8.39-8.36 (m, 1H), 8.20-8.17 (m,1H), 8.01 (d, J=8.8 Hz, 1H), 7.50-7.47 (m, 1H), 6.35 (bs, 1H), 4.02 (t,J=5.8 Hz, 2H), 2.67 (bs, 2H), 2.93-2.89 (m, 2H), 2.73-2.69 (m, 2H), 2.08(bs, 5H). LC-MS: m/z 391 [M+H]⁺.

Synthesis of4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[5-(pyridin-3-yl)pyridin-2-yl]butanamide,Compound 49

¹H NMR (400 MHz, DMSO-d₆) 10.68 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.71(s, 1H), 8.58-8.57 (m, 1H), 8.16-8.12 (m, 3H), 7.51-7.47 (m, 1H), 6.34(br s, 1H), 4.02 (t, J=5.6 Hz, 2H), 3.86 (s, 2H), 2.90-2.87 (m, 2H),2.76-2.73 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 391 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyrazin-2-yl)pyridin-2-yl)butanamide,Compound 50

¹H NMR (400 MHz, Chloroform-d): 9.01 (1H, d, J=1.2 Hz), 8.94 (1H, s),8.63 (1H,t), 8.53 (1H, d, J=2.4 Hz), 8.45 (1H, s), 8.33 (2H, m), 4.16(2H, t), 3.94 (2H, bs), 2.97 (2H, m), 2.87 (2H, t), 2.23 (4H, m), 1.25(3H, s). LC-MS: m/z 392.1 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyridin-3-yl)pyrazin-2-yl)butanamide,Compound 52

¹H NMR (400 MHz, DMSO-d₆): 11.00 (s, 1H), 9.40 (s, 1H), 9.27 (m, 1H),9.08 (m, 1H), 8.65-8.64 (m, 1H), 8.45-8.43 (m, 1H), 7.55-7.52 (m, 1H),6.34 (bs, 1H), 4.03 (t, J=5.8 Hz, 2H), 3.87 (bs, 2H), 2.93-2.90 (m, 2H),2.80-2.77 (m, 2H), 2.08 (bs, 5H). LC-MS: m/z 392 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(3-methyl-[1,1′-biphenyl]-4-yl)-4-oxobutanamide,Compound 53

¹H NMR (400 MHz, DMSO-d₆): 9.38 (s, 1H), 7.65-7.63 (m, 2H), 7.52-7.42(m, 5H), 7.35-7.31 (m, 1H), 6.36 (br s, 1H), 4.02 (t, J=6.0 Hz, 2H),3.86 (s, 2H), 2.89-2.88 (m, 2H), 2.71-2.68 (m, 2H), 2.28 (s, 3H), 2.09(s, 5H). LC-MS: m/z 403 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(2-methyl-[1,1′-biphenyl]-4-yl)-4-oxobutanamide,Compound 54

¹H NMR (400 MHz, DMSO-d₆): 9.99 (s, 1H), 7.52-7.40 (m, 4H), 7.35-7.29(m, 3H), 7.12-7.10 (m, 1H), 6.35 (br s, 1H), 4.02 (t, J=6.0 Hz, 2H),3.86 (s, 2H), 2.89-2.86 (m, 2H), 2.66-2.63 (m, 2H), 2.20 (s, 3H), 2.08(s, 5H). LC-MS: m/z 403 [M+H]⁺.

Synthesis ofN-(3-methoxy-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 55

¹H NMR (400 MHz, DMSO-d₆): 9.22 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.68(d, J=7.2 Hz, 2H), 7.44 (t, J=7.2 Hz, 2H), 7.35-7.33 (m, 1H), 7.28 (s,1H), 7.21-7.18 (m, 1H), 6.35 (br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.94(s, 3H), 3.86 (s, 2H), 2.88-2.85 (m, 2H), 2.75-2.72 (m, 2H), 2.08 (s,5H). LC-MS: m/z 419 [M+H]⁺.

Synthesis ofN-(2-methoxy-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 56

¹H NMR (400 MHz, DMSO-d₆): 10.10 (s, 1H), 7.51 (bs, 1H), 7.46-7.44 (m,2H), 7.37 (t, J=7.6 Hz, 2H), 7.29-7.26 (m, 1H), 7.21 (s, 2H), 6.35 (bs,1H), 4.03 (t, J=5.8 Hz, 2H), 3.87 (bs, 2H), 2.90-2.87 (m, 2H), 2.68-2.64(m, 2H), 2.08 (bs, 5H). LC-MS: m/z 419 [M+H]⁺.

Synthesis ofN-(2-fluorobiphenyl-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 57

¹H NMR (400 MHz, DMSO-d₆): 10.31 (s, 1H), 7.73-7.67 (m, 1H), 7.54-7.42(m, 5H), 7.41-7.34 (m, 2H), 6.35 (bs, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.87(bs, 2H), 2.92-2.83 (m, 2H), 2.70-2.63 (m, 2H), 2.08 (bs, 5H). MS (ESI)m/z 407 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(2′-methyl-[1,1′-biphenyl]-4-yl)-4-oxobutanamide,Compound 58

¹H NMR (400 MHz, DMSO-d₆): 10.08 (s, 1H), 7.66-7.64 (m, 2H), 7.29-7.16(m, 6H), 6.35 (br s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (s, 2H),2.91-2.88 (m, 2H), 2.68-2.65 (m, 2H), 2.23 (s, 3H), 2.09 (s, 5H). LC-MS:m/z 403 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(3′-methyl-[1,1′-biphenyl]-4-yl)-4-oxobutanamide,Compound 59

¹H NMR (400 MHz, DMSO-d₆): 10.09 (s, 1H), 7.69-7.66 (m, 2H), 7.60-7.58(m, 2H), 7.45-7.41 (m, 2H), 7.34-7.30 (m, 1H), 7.14-7.12 (m, 1H), 6.34(br s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (s, 2H), 2.91-2.87 (m, 2H),2.68-2.65 (m, 2H), 2.36 (s, 3H), 2.08 (s, 5H). LC-MS: m/z 403 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4′-methyl-[1,1′-biphenyl]-4-yl)-4-oxobutanamide,Compound 60

¹H NMR (400 MHz, DMSO-d₆): 10.07 (s, 1H), 7.67-7.65 (m, 2H), 7.58-7.51(m, 4H), 7.24 (d, J=8.0 Hz, 2H), 6.34 (bs, 1H), 4.02 (t, J=6.0 Hz, 2H),3.86 (bs, 2H), 2.88 (t, J=6.4 Hz, 2H), 2.67-2.64 (m, 2H), 2.32 (s, 3H),2.08 (bs, 5H). LC-MS: m/z 403 [M+H]⁺.

Synthesis ofN-(2′-methoxy-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 61

¹H NMR (400 MHz, DMSO-d₆): 10.05 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.39(d, J=8.8 Hz, 2H), 7.33-7.25 (m, 2H), 7.08 (d, J=7.6 Hz, 1H), 7.00 (t,J=4.2 Hz, 1H), 6.30 (bs, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.86 (bs, 2H),3.75 (s, 3H), 2.88 (t, J=6.4 Hz, 2H), 2.67-2.64 (m, 2H), 2.08 (bs, 5H).LC-MS: m/z 419 [M+H]⁺.

Synthesis ofN-(3′-methoxy-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 62

¹H NMR (400 MHz, DMSO-d₆): 10.10 (s, 1H), 7.69-7.67 (m, 2H), 7.63-7.60(m, 6H), 7.37-7.33 (m, 1H), 7.21-7.16 (m, 2H), 6.91-6.88 (m, 1H), 6.35(br s, 1H), 4.03 (t, J=5.6 Hz, 2H), 3.87-3.82 (m, 5H), 2.91-2.87 (m,2H), 2.68-2.65 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 419 [M+H]⁺.

Synthesis ofN-(4′-methoxy-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 63

¹H NMR (400 MHz, DMSO-d₆): 10.05 (s, 1H), 7.65-7.63 (m, 2H), 7.58-7.53(m, 4H), 6.99 (d, J=8.8 Hz, 2H), 6.30 (bs, 1H), 4.02 (t, J=6 Hz, 2H),3.87 (bs, 2H), 3.78 (s, 3H), 2.90-2.86 (m, 2H), 2.65 (t, J=6.2 Hz, 2H),2.08 (bs, 5H). LC-MS: m/z 419 [M+H]⁺.

Synthesis ofN-(3′-fluoro-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 65

¹H NMR (400 MHz, DMSO-d₆): 10.13 (s, 1H), 7.71-7.65 (m, 4H), 7.51-7.46(m, 3H), 7.16-7.12 (m, 1H), 6.35 (br, 1H), 4.03 (t, J=5.8 Hz, 2H), 3.87(br, 2H), 2.91-2.88 (m, 2H), 2.68-2.65 (m, 2H), 2.08 (br, 5H). LC-MS:m/z 407 [M+H]⁺.

Synthesis ofN-(4′-fluorobiphenyl-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 66

¹H NMR (400 MHz, DMSO-d₆): 10.10 (s, 1H), 7.70-7.62 (m, 4H), 7.61-7.57(m, 2H), 7.30-7.20 (m, 2H), 6.35 (bs, 1H), 4.02 (t, J=6.4 Hz, 2H), 3.87(bs, 2H), 2.92-2.85 (m, 2H), 2.70-2.63 (m, 2H), 2.08 (bs, 5H); MS (ESI)m/z 407 [M+H]⁺.

Synthesis of4′-(4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamido)-[1,1′-biphenyl]-3-carboxylicacid, Compound 67

¹H NMR (400 MHz, DMSO-d₆): 10.12 (s, 1H), 8.15 (s, 1H), 7.98-7.94 (m,1H), 7.90-7.87 (m, 2H), 7.73-7.64 (m, 4H), 7.56 (t, J=7.6Hz, 1H), 6.35(bs, 1H), 4.03 (t, J=5.8 Hz, 2H), 3.87 (bs, 2H), 2.91-2.88 (m, 2H), 2.67(t, J=6.6Hz, 2H), 2.08 (s, 5H). LC-MS: m/z 433 [M+H]⁺.

Synthesis ofN-(2′-amino-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 69 Step 1: Preparation ofN-(4-bromophenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide

¹H NMR (400 MHz, DMSO-d₆): 10.13 (s, 1H), 7.57-7.55 (m, 2H), 7.47-7.45(m, 2H), 6.33 (br s, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.85 (s, 2H),2.88-2.85 (m, 2H), 2.65-2.61 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 392[M+H]⁺.

Step 2: Preparation ofN-(2′-amino-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide.

The desired product was obtained using general Suzuki procedure A.

¹H NMR (400 MHz, DMSO-d₆): 10.06 (s, 1H), 7.66-7.64 (m, 2H), 7.33-7.31(m, 2H), 7.03-6.94 (m, 2H), 6.74-6.72 (m, 1H), 6.61 (t, J=7.2 Hz, 1H)6.35 (br s, 1H), 4.70 (s, 2H), 4.02 (t, J=6.0 Hz, 2H), 3.86 (s, 2H),2.90-2.87 (m, 2H), 2.67-2.64 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 404[M+H]⁺.

Synthesis ofN-(3′-amino-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 70 Step 1: Preparation of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(2-methyl-[1,1′-biphenyl]-4-yl)-4-oxobutanamide

¹H NMR (400 MHz, DMSO-d₆): 10.17 (s, 1H), 8.41 (s, 1H), 8.18-8.12 (m,2H), 7.75-7.71 (m, 5H), 6.35 (br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.87(s, 2H), 2.91-2.88 (m, 2H), 2.69-2.66 (m, 2H), 2.08 (s, 5H). LC-MS: m/z434 [M+H]⁺.

Step 2: Preparation ofN-(3′-amino-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide

4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-N-[4-(3-nitrophenyl)phenyl]-4-oxobutanamide (1equiv.), ammonium chloride(4 equiv.), and iron(2 equiv.) were added to asolution of ethanol (0.02 M) and water(0.08 M), and heated at 40° C. for4 h. The reaction mixture was then filtered, diluted with water andextracted with ethyl acetate. The combined organic layers were driedover magnesium sulphate and concentrated under vacuum. The crude productwas purified by reversed phase preparative HPLC to afford the purifiedproduct.

¹H NMR (400 MHz, DMSO-d₆): 10.05 (s, 1H), 7.65-7.63 (m, 2H), 7.49-7.47(m, 2H), 7.06 (t, J=7.6 Hz, 1H), 6.80 (s, 1H), 6.75-6.73 (m, 1H),6.52-6.50 (m, 1H), 6.34 (br s, 1H), 5.09 (s, 2H), 4.02 (t, J=6.0 Hz,2H), 3.86 (s, 2H), 2.89-2.86 (m, 2H), 2.67-2.63 (m, 2H), 2.08 (s, 5H).LC-MS: m/z 404 [M+H]⁺.

Synthesis ofN-(4′-amino-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 71 Step 1: Preparation of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4′-nitro-[1,1′-biphenyl]-4-yl)-4-oxobutanamide

MS: m/z 434 [M+H]⁺.

Step 2: Preparation ofN-(4′-amino-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide

The desired product was obtained in a similar fashion as compound 70.

¹H NMR (400 MHz, DMSO-d₆): 9.97 (s, 1H), 7.60-7.58 (m, 2H), 7.47-7.45(m, 2H), 7.36-7.34 (m, 2H), 6.67 (d, J=8.0 Hz, 2H), 6.34 (br s, 1H),5.70-5.60 (br s, 2H), 4.02 (t, J=5.6 Hz, 2H), 3.86 (s, 2H), 2.89-2.86(m, 2H), 2.65-2.62 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 404 [M+H]⁺.

Synthesis ofN-(3′-(dimethylamino)-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 72

¹H NMR (400 MHz, DMSO-d₆): 10.03(s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.45(d, J=8.4 Hz, 2H), 7.25-7.21 (m, 1H), 7.14-7.12 (m, 1H), 7.04-6.96 (m,2H), 6.34 (bs, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.87 (bs, 2H), 2.90-2.87 (m,2H), 2.67-2.64 (m, 2H), 2.47 (s, 6H), 2.08 (bs, 5H). LC-MS: m/z 432[M+H]⁺.

Synthesis ofN-(3′-acetamido-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 74

N-[4-(3-aminophenyl)phenyl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxobutanamide(1 equiv.) was dissolved indichloromethane(0.02 M) at 0° C. Triethylamine(1 equiv.), followed byacetyl chloride(1.05 equiv.), was added to the solution, and thereaction mixture allowed to stir for 30 min. It was then diluted withwater and extracted with dichloromethane. The combined organic layerswere dried over magnesium sulphate and concentrated under vacuum. Thecrude product was purified by reversed phase preparative HPLC to affordthe purified product.

¹H NMR (400 MHz, DMSO-d₆) 10.09 (s, 1H), 9.98 (s, 1H), 7.83 (s, 1H),7.69-7.67 (m, 2H), 7.54-7.52 (m, 3H), 7.36-7.27 (m, 2H), 6.34 (br s,1H), 4.03 (t, J=6.0 Hz, 2H), 3.86 (s, 2H), 2.90-2.87 (m, 2H), 2.67-2.64(m, 2H), 2.08-2.05 (m, 8H). LC-MS: m/z 446 [M+H]⁺.

Synthesis ofN-(4-cyclohexylphenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 75

¹H NMR (400 MHz, DMSO-d₆): 9.88 (s, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.11(d, J=8.4 Hz, 2H), 6.34 (bs, 1H), 4.02 (t, J=5.6 Hz, 2H), 3.85 (bs, 2H),2.87-2.84 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.42 (m, 1H), 2.08 (bs, 5H),1.76-1.67 (m, 5H), 1.41-1.19 (m, 5H). LC-MS: m/z 395 [M+H]⁺.

Synthesis of tert-butyl4-(4-(4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamido)phenyl)piperazine-1-carboxylate,Compound 76

¹H NMR (400 MHz, DMSO-d₆): 9.77 (s, 1H), 7.44 (d, J=8.8 Hz, 2H), 6.88(d, J=9.2 Hz, 2H), 6.30 (bs, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.85 (bs, 2H),3.45-3.43 (m, 4H), 3.02-2.99 (m, 4H), 2.87-2.83 (m, 2H), 2.60-2.57 (m,2H), 2.08 (bs, 5H), 1.42 (s, 9H). LC-MS: m/z 497 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(piperazin-1-yl)phenyl)butanamide,Compound 77

4M HCl in dioxane (15 equiv.) was added to the boc-protected amine (1equiv.) and stirred at room temperature for 16 h. Upon completion,reaction was extracted with saturated sodium bicarbonate, organic layerscombined, dried over magnesium sulphate, filtered and concentrated todryness in vacuo. Crude was purified by recrystallisation withdichloromethane/hexane and lyophilized to afford pure product as an offwhite solid.

¹H NMR (400 MHz, DMSO-d₆): 9.73 (s, 1H), 7.42 (d, J=8.8 Hz, 2H), 6.84(d, J=8.8 Hz, 2H), 6.34 (bs, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.85 (bs, 2H),2.98-2.95 (m, 4H), 2.84-2.81 (m, 6H), 2.58 (t, J=6.6 Hz, 2H), 2.08 (bs,5H). LC-MS: m/z 397 [M+H]⁺.

Synthesis ofN-(4-(4-acetylpiperazin-1-yl)phenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 78

A solution of compound 77 (1.0 equiv.) in dry tetrahydrofuran was addedto a stirred mixture of acid chloride (1.0 equiv.) and triethylamine(1.2 equiv.) in tetrahydrofuran at 0° C. The reaction mixture wasallowed to warm to room temperature with continued stirring for 3 h.Upon completion of reaction, solvent was evaporated to dryness in vacuoand crude extracted with ethyl acetate and dried over magnesiumsulphate. Crude was purified by crashing out solids withDCM/methano;/hexane to afford a white solid.

¹H NMR (400 MHz, DMSO-d₆): 9.77 (s, 1H), 7.45 (d, J=9.2 Hz, 2H), 6.89(d, J=9.2 Hz, 2H), 6.30 (bs, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.85 (bs, 2H),3.57-3.54 (m, 4H), 3.08-3.06 (m, 2H), 3.01-2.99 (m, 2H), 2.87-2.84 (m,2H), 2.59 (t, J=6.6 Hz, 2H), 2.08 (bs, 5H), 2.03 (s, 3H). LC-MS: m/z 439[M+H]⁺.

Synthesis ofN-ethyl-4-(6-(4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamido)pyridin-3-yl)piperazine-1-carboxamide,Compound 79

Step 1: Preparation of tert-butyl4-(6-(4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamido)pyridin-3-yl)piperazine-1-carboxylate

LC-MS: m/z 498 [M+H]⁺.

Step 2: Preparation of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(piperazin-1-yl)pyridin-2-yl)butanamide

To a stirred solution of tert-butyl4-(6-(4-(2-methyl-6,7-dihydropyrazolo[1,5-c]pyrimidin-4(5H)-yl)-4-oxobutanamido)pyridin-3-yl)piperazine-1-carboxylate(1 equiv.) in dichloromethane (0.04M) was added TFA (5 equiv.) drop-wiseat 0° C. and stirred at room temperature for 1 h. The reaction mixturewas diluted with water and basified with saturated sodium bicarbonatesolution and then extracted with dichloromethane. The organic layer wasdried over anhydrous sodium sulphate and concentrated under reducedpressure to afford the intermediate.

LC-MS: m/z 398 [M+H]⁺.

Step 3: Preparation ofN-ethyl-4-(6-(4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamido)pyridin-3-yl)piperazine-1-carboxamide

To a stirred solution of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(piperazin-1-yl)pyridin-2-yl)butanamide(1 equiv.) in THF (0.015 M) was added ethylisocyanate (4.5 equiv.) andthe reaction mixture was stirred at 80° C. in sealed tube for 16 h. Thereaction mixture was concentrated under reduced pressure to give crudeproduct. The crude product was purified by preparative TLC to afford theproduct.

¹H NMR (400 MHz, DMSO-d₆): 10.25 (s, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.92(d, J=8.3 Hz, 1H), 7.41-7.39 (dd, J=2.7 Hz, 9.3 Hz, 1H), 6.53-6.55 (m,1H), 6.32 (brs, 1H), 4.01 (t, J=5.7 Hz, 2H), 3.84 (brs, 2H), 3.39-3.41(m, 4H), 3.05-3.07 (m, 6H), 2.82-2.84 (m, 2H), 2.64-2.66 (m, 2H), 2.07(brs, 5H), 1.01 (t, J=7.5 Hz, 3H). MS (ESI) m/z 469.2 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-phenylcyclohexyl)butanamide,Compound 80

¹H NMR (400 MHz, DMSO-d₆): 7.78 (d, J=7.6 Hz, 1H), 7.30-7.21 (m, 4H),7.19-7.13 (m, 1H), 6.35 (bs, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.83 (bs, 2H),3.65-3.52 (m, 1H), 2.80-2.70 (m, 2H), 2.50-2.40 (m, 2H), 2.40-2.35 (m,2H), 2.08 (m, 5H), 1.90-1.82 (m, 2H), 1.82-1.75 (m, 2H), 1.57-1.45 (m,2H), 1.38-1.25 (m, 2H); MS (ESI) m/z 395 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxobutanamide,Compound 82

¹H NMR (400 MHz, DMSO-d₆): 9.90 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.14(d, J=8.4 Hz, 2H), 6.33 (bs, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.85 (bs, 2H),2.88-2.86 (m, 5H), 2.61 (t, J=6.6 Hz, 2H), 2.20 (s, 3H), 2.08 (bs, 5H),2.01-1.95 (m, 2H), 1.71-1.60 (m, 4H). LC-MS: m/z 410 [M+H]⁺.

Synthesis ofN-(6-(3-chlorophenyl)pyridin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 83

¹H NMR (400 MHz, Methanol-d₄): 8.80-8.81 (m, 1H), 8.18-8.20 (m, 1H),7.97-7.98 (m, 1H), 7.82-7.87 (m, 2H), 7.38-7.47 (m, 2H), 4.55 (s, 1H),4.19 (t, J=6.0 Hz, 2H), 3.94-3.96 (m, 2H), 2.99-3.01 (m, 2H), 2.82 (t,J=6.0 Hz, 2H), 2.22 (bs, 2H), 2.18 (s, 3H). LC-MS: m/z 424 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(m-tolyl)pyridin-3-yl)butanamide,Compound 85

¹H NMR (400 MHz, DMSO-d₆): 10.31 (s, 1H), 8.81-8.80 (m, 1H), 8.14-8.11(m, 1H), 7.91-7.87 (m, 2H), 7.82-7.80 (m, 1H), 7.34 (t, J=7.6 Hz, 1H),7.21-7.19 (m, 1H), 6.35 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (bs, 2H),2.92-2.89 (m, 2H), 2.71-2.68 (m, 2H), 2.38 (s, 3H), 2.08 (bs, 5H).LC-MS: m/z 404 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-methyl-6-phenylpyridin-3-yl)-4-oxobutanamide,Compound 86

¹H NMR (400 MHz, DMSO-d₆): 10.24 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 7.97(d, J=2.4 Hz, 1H), 7.52-7.48 (m, 2H), 7.48-7.40 (m, 2H), 7.40-7.35 (m,1H), 6.35 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (bs, 2H), 2.95-2.85 (m,2H), 2.75-2.65 (m, 2H), 2.31 (s, 3H), 2.08 (bs, 5H). MS (ESI) m/z 404[M+H]⁺.

Synthesis ofN-(6-(4-fluorophenyl)pyridin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 87

¹H NMR (400 MHz, DMSO-d₆): 10.33 (s, 1H), 8.81-8.80 (m, 1H), 8.13-8.05(m, 3H), 7.90 (d, J=8.4 Hz, 1H), 7.28 (t, 8.8 Hz, 2H), 6.34 (bs, 1H),4.02 (t, J=6.0 Hz, 2H), 3.86 (bs, 2H), 2.92-2.88 (m, 2H), 2.70-2.67 (m,2H), 2.08 (bs, 5H). LC-MS: m/z 408 [M+H]⁺.

Synthesis ofN-(6-(3-fluorophenyl)pyridazin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 88

¹H NMR (400 MHz, DMSO-d₆): 10.67 (s, 1H), 8.68 (s, 1H),8.13-8.10 (m,2H), 7.80 (s, 1H), 7.70-7.68 (m, 1H), 7.52-7.48 (m, 1H), 7.44-7.42 (m,1H), 6.33 (br s, 1H), 4.02 (t, J=6.0Hz, 2H), 3.86 (s, 2H), 2.90-2.87 (m,2H), 2.75-2.72 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 424 [M+H]⁺.

Synthesis ofN-(5-(3-fluorophenyl)pyridin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 89

¹H NMR (400 MHz, DMSO-d₆): 10.67 (s, 1H), 8.69 (s, 1H), 8.13 (s, 2H),7.61-7.48 (m, 3H), 7.23-7.18 (m, 1H), 6.33 (bs, 1H), 4.02 (t, J=5.8 Hz,2H), 3.86 (bs, 2H), 2.91-2.87 (m, 2H), 2.76-2.72 (m, 2H), 2.08 (bs, 5H).LC-MS: m/z 408 [M+H]⁺.

Synthesis ofN-(5-(4-fluorophenyl)pyridin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 90

¹H NMR (400 MHz, DMSO-d₆): 10.62 (s, 1H), 8.62-8.63 (m, 1H), 8.12-8.14(m, 1H), 8.04-8.07 (m, 1H), 7.73-7.77 (m, 2H), 7.28-7.32 (m, 2H), 6.34(bs, 1H), 4.55 (s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.85-3.87 (m, 2H),2.87-2.90 (m, 2H), 2.73 (t, J=6.0 Hz, 2H), 2.22 (bs, 2H), 2.08 (s, 3H).LC-MS: m/z 408 [M+H]⁺.

Synthesis ofN-(3-methyl-5-phenylpyridin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 91

¹H NMR (400 MHz, DMSO-d₆): 10.07 (s, 1H), 8.53 (s, 1H), 7.94 (s, 1H),7.72-7.70 (m, 2H), 7.51-7.47 (m, 2H), 7.42-7.38 (m, 1H), 6.35 (br s,1H), 4.01 (t, J=6.0 Hz, 2H), 3.85 (s, 2H), 2.89-2.86 (m, 2H), 2.71-2.68(m, 2H), 2.21 (s, 3H), 2.09 (s, 5H). LC-MS: m/z 404 [M+H]⁺.

Synthesis ofN-(4-methyl-5-phenylpyridin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 92

¹H NMR (400 MHz, DMSO-d₆): 10.55 (s, 1H), 8.61 (s, 2H), 8.16 (s, 1H),8.05 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.47 (m, 1H), 6.33 (s, 1H),4.02 (t, J=6.0 Hz, 2H), 3.86 (s, 2H), 2.88 (s, 2H), 2.73 (d, J=6.4 Hz,2H), 2.24 (s, 3H), 2.08 (bs, 5H). MS (ESI) m/z 404.1 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(m-tolyl)pyridin-2-yl)butanamide,Compound 93

¹H NMR (400 MHz, DMSO-d₆): 10.63 (s, 1H), 8.63-8.622 (m, 1H), 8.14-8.12(m, 1H), 8.07-8.04 (m, 1H), 7.53 (bs, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.36(t, J=7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.34 (bs, 1H), 4.02 (t, J=6.0Hz, 2H), 3.87 (bs, 2H), 2.90-2.87 (m, 2H), 2.75-2.72 (m, 2H), 2.38 (s,3H), 2.08 (bs, 5H). LC-MS: m/z 404 [M+H]⁺.

Synthesis ofN-(5-fluoro-2,3′-bipyridin-6′-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 94

¹H NMR (400 MHz, DMSO-d₆): 10.72 (s, 1H), 8.99 (d, J=2.4 Hz, 1H), 8.66(d, J=2.8 Hz, 1H), 8.43-8.38 (m, 1H), 8.19-8.14 (m, 1H), 8.12-8.07 (m,1H), 7.84 (td, J=8.8, 3.2 Hz, 1H), 6.34 (bs, 1H), 4.02 (t, J=6.0 Hz,2H), 3.86 (bs, 2H), 2.92-2.85 (m, 2H), 2.78-2.72 (m, 2H), 2.08 (bs, 5H).MS (ESI) m/z 409 [M+H]⁺.

Synthesis ofN-(4-fluoro-2,3′-bipyridin-6′-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 95

¹H NMR (400 MHz, DMSO-d₆): 10.75 (s, 1H), 9.07 (d, J=1.7 Hz, 1H),8.70-8.67 (dd, J=5.7 Hz, 9.2 Hz, 1H), 8.48-8.46 (dd, J=2.2 Hz, 8.8 Hz,1H), 8.18 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.31-7.28 (m, 1H),6.33 (brs, 1H), 4.04-4.01 (t, J=5.7 Hz, 2H), 3.86 (brs, 2H), 2.89 (d,J=6.1 Hz, 2H), 2.76 (t, J=6.2 Hz, 2H), 2.08 (brs, 5H). MS (ESI) m/z409.11 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(6-methyl-[2,3′-bipyridin]-6′-yl)-4-oxobutanamide,Compound 96

¹H NMR (400 MHz, DMSO-d₆): 10.71 (s, 1H), 9.01-9.00 (m, 1H), 8.42-8.40(m, 1H), 8.17-8.15 (d, J=8.8 Hz, 1H), 7.80-7.75 (m, 2H), 7.23-7.21 (m,1H), 6.33 (br, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.86 (br, 2H), 2.89-2.87 (m,2H), 2.75-2.72 (m, 2H), 2.54 (s, 3H), 2.08 (br, 5H). LC-MS: m/z 405[M+H]⁺.

Synthesis ofN-(6-(3-chlorophenyl)pyridazin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 97

¹H NMR (400 MHz, Methanol-d₄): 8.50-8.53 (m, 1H), 8.08-8.13 (m, 2H),7.94-7.95 (m, 1H), 7.50-7.52 (m, 1H), 4.55 (s, 1H), 4.11 (t, J=6.0 Hz,2H), 3.95-3.97 (m, 2H), 3.00-3.02 (m, 2H), 2.91 (t, J=6.0 Hz, 2H), 2.22(bs, 2H), 2.18 (s, 3H). LC-MS: m/z 425 [M+H]⁺.

Synthesis ofN-[6-(4-chlorophenyl)pyridazin-3-yl]-4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxobutanamide,Compound 100

¹H NMR (400 MHz, DMSO-d₆): 11.29 (s, 1H), 8.37 (d, J=9.2 Hz, 1H), 8.24(d, J=9.6 Hz, 1H), 8.13 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 4.02(t, J=6.0 Hz, 2H), 3.86 (s, 2H), 2.91-2.89 (m, 2H), 2.81-2.78 (m, 2H),2.07 (s, 5H). LC-MS: m/z 426 [M+H]⁺.

Synthesis ofN-(6-(4-fluorophenyl)pyridazin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 101

¹H NMR (400 MHz, Chloroform-d): 9.17 (1H, bs), 8.50 (1H, d, J=9.2 Hz),8.00-8.04 (2H, m), 7.82 (1H, d, J=9.2 Hz), 7.19 (2H, t), 4.16 (2H, t),3.94 (2H, bs), 2.96-3.06(4H, m), 2.23 (5H, m). LC-MS: m/z 409.2 [M+H]⁺.

Synthesis ofN-(6-(5-chloropyridin-3-yl)pyridazin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 102

¹H NMR (400 MHz, DMSO-d₆): 11.36 (s, 1H), 9.24 (d, J=1.7 Hz, 1H), 8.75(d, J=2.2 Hz, 1H), 8.59 (t, J=2.2 Hz, 1H), 8.38 (q, J=9.2 Hz, 17.1 Hz,2H), 6.35 (br s, 1H), 4.03 (t, J=6.1 Hz, 2H), 3.86 (br s, 2H), 2.91-2.90(m, 2H), 2.83-2.80 (m, 2H), 2.08 (br s, 5H). MS (ESI) m/z 426.24 [M+H]⁺.

Synthesis ofN-(5′-chloro-[2,3′-bipyridin]-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 108

¹H NMR (400 MHz, Chloroform-d): 9.02 (1H, bs), 8.68 (1H, s), 8.57 (1H,d, J=2.4 Hz), 8.29-8.32 (3H, m), 7.73 (1H, d, J=8.8 Hz), 4.16 (2H, t),3.94 (2H, bs), 2.97 (2H, m), 2.89 (2H, t), 2.24 (5H, m). LC-MS: m/z425.1 [M+H]⁺.

Synthesis ofN-(5′-fluoro-[2,3′-bipyridin]-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 109

¹H NMR (400 MHz, DMSO-d₆): 10.43 (s, 1H), 9.12 (s, 1H), 8.87 (d, J=2.0Hz, 1H), 8.59 (d, J=2.8 Hz, 1H), 8.29-8.25 (m, 1H), 8.21-8.18 (m, 1H),8.10-8.08 (m, 1H), 6.34 (br s, 1H), 4.02 (t, J=6.4 Hz, 2H), 3.86 (s,2H), 2.92-2.89 (m, 2H), 2.72-2.69 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 409[M+H]⁺.

Synthesis ofN-(3-fluoro-2,3′-bipyridin-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 111

¹H NMR (400 MHz, DMSO-d₆): 10.68 (s, 1H), 9.05 (s, 1H), 8.68 (s, 1H),8.70-8.65 (m, 1H), 8.30-8.15 (m, 2H), 7.55-7.50 (s, 1H), 6.35 (bs, 1H),4.10-4.00 (m, 2H), 3.87 (bs, 2H), 3.00-2.85 (m, 2H), 2.80-2.65 (m, 2H),2.08 (bs, 5H). MS (ESI) m/z 409 [M+H]⁺.

Synthesis ofN-(5′-amino-2,3′-bipyridin-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 112

¹H NMR (400 MHz, DMSO-d₆): 10.38 (s, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.35(d, J=1.6 Hz, 1H), 8.12-8.09 (m, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.88-7.82(m, 1H), 7.58-7.52 (m, 1H), 6.35 (bs, 1H), 5.40 (s, 2H), 4.03 (t, J=6.0Hz, 2H), 3.87 (bs, 2H), 2.95-2.85 (m, 2H), 2.75-2.65 (m, 2H), 2.08 (bs,5H); MS (ESI) m/z 406 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(6′-methyl-[2,3′-bipyridin]-5-yl)-4-oxobutanamide,Compound 113

¹H NMR (400 MHz, DMSO-d₆): 10.36 (s, 1H), 9.08-9.07 (m, 1H), 8.83-8.82(m, 1H), 8.27-8.25 (m, 1H), 8.16-8.13 (m, 1H), 7.96 (d, J=8.8 Hz, 1H),7.34 (d, J=8.0 Hz, 1H), 6.34 (bs, 1H), 4.02 (t, J=5.6 Hz, 2H), 3.86 (bs,2H), 2.92-2.89 (m, 2H), 2.69 (m, 2H), 2.08 (bs, 5H). LC-MS: m/z 405[M+H]⁺.

Synthesis ofN-(5′-chloro-[3,3′-bipyridin]-6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 114

¹H NMR (400 MHz, DMSO-d₆): 10.73 (s, 1H), 8.92 (d, J=1.6 Hz, 1H), 8.78(d, J=1.6 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.34-8.33 (m, 1H), 8.23-8.15(m, 2H), 6.33 (br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.86 (s, 2H),2.90-2.87 (m, 2H), 2.76-2.73 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 425[M+H]⁺.

Synthesis ofN-(5′-fluoro-[3,3′-bipyridin]-6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 115

¹H NMR (400 MHz, DMSO-d₆): 10.73 (s, 1H), 8.86 (t, J=1.6 Hz, 1H), 8.78(d, J=2.0 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.24-8.13 (m, 3H), 6.30 (bs,1H), 4.03 (t, J=5.8 Hz, 2H), 3.86 (bs, 2H), 2.91-2.88 (m, 2H), 2.76-2.73(m, 2H), 2.08 (bs, 5H). LC-MS: m/z 409 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide,Compound 116

¹H NMR (400 MHz, DMSO-d₆): 10.68 (s, 1H), 8.74-8.70 (m, 2H), 8.42 (s,1H), 8.18-8.12 (m, 2H), 7.96 (s, 1H), 6.34 (bs, 1H), 4.03 (t, J=5.8 Hz,2H), 3.87 (bs, 2H), 2.90-2.87(m, 2H), 2.76-2.73 (m, 2H), 2.37 (s, 3H),2.08 (bs, 5H). LC-MS: m/z 405 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(piperazin-1-yl)phenyl)butanamide,Compound 117 Step 1: Preparation of Boc-protected4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(piperazin-1-yl)phenyl)butanamide

¹H NMR (400 MHz, DMSO-d₆): 10.71 (s, 1H), 8.90 (m, 1H), 8.75 (bs, 1H),8.44-8.43 (d, J=2.4 Hz, 1H), 8.19-8.15 (m, 3H), 6.36 (bs, 1H), 4.02 (t,J=6.0 Hz, 2H), 3.86 (bs, 2H), 2.91-2.87 (m, 2H), 2.76-2.73 (m, 2H), 2.08(bs, 5H), 1.40 (s, 18H). LC-MS: m/z 606 [M+H]⁺.

Step 2: Preparation of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(piperazin-1-yl)phenyl)butanamide

¹H NMR (400 MHz, DMSO-d₆): 10.64 (s, 1H), 8.56 (m, 1H), 8.14 (d, J=8.4Hz, 1H), 8.06-8.05 (m, 1H), 8.01-7.99 (m, 1H), 7.94 (d, J=2.4 Hz, 1H),7.16 (t, J=2.2 Hz, 1H), 6.33 (bs, 1H), 5.41 (s, 2H), 4.02 (t, J=6.0 Hz,2H), 3.86 (bs, 2H), 2.90-2.87 (m, 2H), 2.75-2.72 (m, 2H), 2.08 (bs, 5H).LC-MS: m/z 406 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)butanamide,Compound 118

¹H NMR (400 MHz, DMSO-d₆): 10.77 (s, 1H), 9.27-9.26 (m, 1H), 8.97 (bs,1H), 8.85-8.84 (m, 1H), 8.56 (bs, 1H), 8.31-8.28 (m, 1H), 8.20-8.18 (m,1H), 6.34 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.86 (bs, 2H), 2.91-2.88 (m,2H), 2.77-2.74 (m, 2H), 2.08 (bs, 5H). LC-MS: m/z 459 [M+H]⁺.

Synthesis ofN-(4-methyl-3,3′-bipyridin-6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 119

¹H NMR (400 MHz, DMSO-d₆): 10.56 (s, 1H), 8.61 (s, 2H), 8.16 (s, 1H),8.05 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.47 (m, 1H), 6.33 (s, 1H),4.02 (t, J=6.0 Hz, 2H), 3.86 (s, 2H), 2.87 (d, J=5.6 Hz, 2H), 2.73 (d,J=6.0 Hz, 2H), 2.25 (s, 3H), 2.08 (s, 5H); MS (ESI) m/z 405.39 [M+H]⁺.

Synthesis ofN-(4,5′-dimethyl-3,3′-bipyridin-6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 120

¹H NMR (400 MHz, DMSO-d₆): 10.57 (s, 1H), 8.44 (d, J=1.2 Hz, 1H), 8.40(d, J=1.2 Hz, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.67 (s, 1H), 6.35 (bs,1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (bs, 2H), 2.90-2.80 (m, 2H), 2.80-2.60(m, 2H), 2.36 (s, 3H), 2.26 (s, 3H), 2.08 (bs, 5H). MS (ESI) m/z 419[M+H]⁺.

Synthesis ofN-(6′-methyl-3,3′-bipyridin-6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 121

¹H NMR (400 MHz, Methanol-d₄): 8.68 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0Hz, 1H), 8.22-8.18 (m, 1H), 8.08-7.98 (m, 2H), 7.41 (d, J=8.0 Hz, 1H),4.56 (s, 1H), 4.11 (t, J=6.8 Hz, 2H), 3.96 (bs, 2H), 3.03-2.95 (m, 2H),2.90-2.83 (m, 2H), 2.58 (s, 3H), 2.30-2.15 (m, 5H); MS (ESI) m/z 405[M+H]⁺.

Synthesis ofN-(5-(5-fluoropyridin-3-yl)pyrazin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 122

¹H NMR (400 MHz, DMSO-d₆): 11.06 (s, 1H), 9.42 (d, J=1.2 Hz, 1H), 9.18(t, J=1.6 Hz, 1H), 9.14 (d, J=1.2 Hz, 1H), 8.66 (d, J=2.8 Hz, 1H),8.40-8.30 (m, 1H), 6.33 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (bs, 2H),2.95-2.85 (m, 2H), 2.85-2.75 (m, 2H), 2.08 (bs, 5H). MS (ESI) m/z 410[M+H]⁺.

Synthesis ofN-(5-(3-fluorophenyl)pyrazin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 123

¹H NMR (400 MHz, DMSO-d₆) 10.98 (s, 1H), 9.37 (s, 1H), 9.05 (d, J=1.2Hz, 1H), 7.97-7.89 (m, 2H), 7.58-7.52 (m, 1H), 7.30-7.28 (m, 1H), 6.33(br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.86 (s, 2H), 3.27 (s, 1H),2.93-2.90 (m, 2H), 2.79-2.76 (m, 2H), 2.07 (s. 3H). LC-MS: m/z 409[M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-(5-methylpyridin-3-yl)pyrazin-2-yl)-4-oxobutanamide,Compound 124

¹H NMR (400 MHz, DMSO-d₆): 10.98 (s, 1H), 9.39 (s, 2H), 9.06 (s, 2H),8.48 (s, 1H), 8.27 (s, 1H), 6.33 (s, 1H), 4.02 (t, J=5.6 Hz, 2H), 3.86(s, 2H), 2.91-2.88 (m, 2H), 2.50-2.75 (m, 2H), 2.39 (bs, 3H), 2.08 (bs,5H); MS (ESI) m/z 404.10 [M +H]⁺.

Synthesis ofN-(6-methyl-5-(pyridin-3-yl)pyrazin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 125

¹H NMR (400 MHz, DMSO-d₆): 10.95 (s, 1H), 9.24 (s, 1H), 8.83-8.82 (m,1H), 8.65-8.63 (m, 1H), 8.07-8.04 (m, 1H), 7.54-7.51 (m, 1H), 6.34 (bs,1H), 4.02 (t, J=6.0 z, 2H), 3.86 (bs, 2H), 2.92-2.89 (m, 2H), 2.78-2.75(m, 2H), 2.54 (s, 3H), 2.08 (bs, 5H). LC-MS: m/z 406 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(m-tolyl)pyrazin-2-yl)butanamide,Compound 126

¹H NMR (400 MHz, DMSO-d₆): 10.91 (s, 1H), 9.35 (s, 1H),8.97 (s, 1H),7.92-7.86 (m, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.26 (d, J=6.8 Hz, 1H), 6.34(br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.86 (s, 2H), 2.91-2.89 (m, 2H),2.78-2.75 (m, 2H), 2.39 (s, 3H), 2.08 (s, 5H). LC-MS: m/z 405 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyridin-3-yl)pyrazin-2-yl)-4-oxobutanamide,Compound 127

¹H NMR (400 MHz, DMSO-d₆): 10.97 (s, 1H), 9.38 (s, 1H), 9.13 (d, J=2.0Hz, 1H), 9.04 (d, J=1.2 Hz, 1H), 8.33 (dd, J=8.0, 2.4 Hz, 1H), 7.39 (d,J=8.0 Hz, 1H), 6.35 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (bs, 2H),2.95-2.85 (m, 2H), 2.80-2.70 (m, 2H), 2.53 (s, 3H), 2.08 (bs, 5H). MS(ESI) m/z 406 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyrazin-2-yl)pyridin-2-yl)-4-oxobutanamide,Compound 128

¹H NMR (400 MHz, DMSO-d₆): 10.79 (s, 1H), 9.08-9.06 (m, 2H), 8.51 (bs,1H), 8.49-8.46 (m, 1H), 8.20 (d, J=8.8 Hz, 1H), 6.33 (bs, 1H), 4.02 (t,J=5.8 Hz, 2H), 3.86 (bs, 2H), 2.91-2.87 (m, 2H), 2.76-2.73 (m, 2H), 2.57(s, 3H), 2.08 (bs, 5H). LC-MS: m/z 406 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrazin-2-yl)phenyl)butanamide,Compound 129

¹H NMR (400 MHz, DMSO-d₆): 10.24 (s, 1H), 9.21 (d, J=1.6 Hz, 1H),8.68-8.65 (m, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.12-8.08 (m, 2H), 7.80-7.72(m, 2H), 6.35 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87 (bs, 2H), 2.95-2.85(m, 2H), 2.72-2.65 (m, 2H), 2.08 (bs, 5H). MS (ESI) m/z 391 [M+H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-N-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 130

Step 1: Preparation ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide

¹H NMR (400 MHz, Methanol-d₄): 7.66 (s, 1H), 7.60-7.58 (m, 1H),7.33-7.29 (m, 2H), 6.53 (s, 1H), 6.13 (brs, 1H), 3.81 (brs, 2H), 3.64(s, 1H), 2.70 (brs, 2H), 2.52-2.51 (m, 2H), 2.29 (s, 2H), 1.86 (brs,5H). LC-MS: MS m/z 414 [M+H]⁺.

Step 2: Preparation ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-N-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide

To a stirred solution ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide(1 equiv.) in dry tetrahydrofuran was added K₂CO₃ (3 equiv.) at roomtemperature and stirring was continued for 15 minutes. CH₃I (5 equiv.)was added to reaction mixture drop wise at 0° C. followed by stirring atroom temperature for 16 h. After completion, the reaction mixture wasdiluted with water and extracted with ethyl acetate. The combinedorganic layer was washed with water and brine solution. The organicsolvent was dried over anhydrous sodium sulphate, filtered andconcentrated under vacuum to give crude product. The crude product waspurified by column chromatography.

¹H NMR (400 MHz, DMSO-d₆): 7.93 (s, 1H), 7.85 (d, J=7.1 Hz, 1H),7.60-7.53 (m, 2H), 7.05 (s, 2H), 6.33 (bs, 1H), 4.02 (bs, 2H), 3.86 (bs,2H), 3.40 (s, 3H), 2.87 (bs, 4H), 2.07 (bs, 5H); MS (ESI) m/z 428.20[M+H]⁺.

Synthesis of3-(3-chlorophenyl)-N-(4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)butyl)isoxazol-5-amine,Compound 131 Step 1: Preparation ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide

¹H NMR (400 MHz, DMSO-d₆): 11.88 (s, 1H), 7.91 (s, 1H), 7.82 (d, 1H),7.58-7.51 (m, 2H), 6.89 (s, 1H), 6.36 (brs, 1H), 4.02 (t, 2H), 3.86(brs, 2H), 2.92 (t, 2H), 2.71 (q, 2H), 2.07 (brs, 5H). LC-MS: MS m/z 414[M+H]⁺.

Step 2: Preparation of3-(3-chlorophenyl)-N-(4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)butyl)isoxazol-5-amine

A solution ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide(1 equiv.) in THF (0.03 M) was treated with borane.DMS (5 equiv.) at 0°C. and the reaction mixture was heated to 40° C. for 10 h. Aftercompletion, the reaction mixture was quenched with methanol andconcentrated under reduced pressure to obtain the crude product; waterwas added and extracted with ethyl acetate. The combined ethyl acetatelayers were dried over sodium sulphate, filtered and concentrated underreduced pressure to obtain the crude product. The crude product waspurified by preparative HPLC.

¹H NMR (400 MHz, Chloroform-d): 7.72 (brs, 1H), 7.62 (d, J=6.8 Hz, 1H),7.37-7.33 (m, 2H), 5.26 (s, 1H), 5.16 (s, 1H), 4.61 (brs, 1H), 4.06 (t,J=6.0 Hz, 2H), 3.29 (d, J=5.6 Hz, 2H), 3.16 (brs, 4H), 2.20 (s, 3H),2.16 (t, J=5.6 Hz, 2H), 1.69 (brs, 4H). LC-MS: MS m/z 386 [M+H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-3-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 132 Step 1: Preparation of 4-methoxy-2-methyl-4-oxobutanoicacid

To a solution of 4-methoxy-2-methylene-4-oxobutanoic acid (1 equiv.) inmethanol (0.3 M) was added a slurry of 10% Pd/C (0.1 equiv.) in methanolunder nitrogen. The reaction mixture was hydrogenated under H₂ (balloon)at room temperature for 16 h. The reaction mixture was filtered throughcelite bed and washed with methanol. The filtrate was concentrated underreduced pressure to give crude product. The crude product was washedwith n-pentane and diethyl ether to remove solid impurities. The solventwas evaporated under reduced pressure to afford the intermediate as apale yellow liquid.

Step 2: Preparation of methyl3-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoate

To a stirred solution of 4-methoxy-2-methyl-4-oxobutanoic acid (1equiv.), 2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1 equiv.)in DMF (0.5 M) was added HATU (1.5 equiv.), TEA (3 equiv.) and thereaction mixture was stirred at rt for 12 h. Upon completion ofreaction, the reaction mixture was added to the ice-water and extractedwith ethyl acetate. The combined organic layer was washed with water,brine, dried over sodium sulphate, filtered and concentrated underreduced pressure to give the crude product. The crude product waspurified by column chromatography to afford the intermediate. LC-MS: MSm/z 266 [M+H]⁺.

Step 3: Preparation of3-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoicacid

To a stirred solution of methyl3-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoate(1 equiv.) in THF—CH₃OH—H₂O (1:1:1) (0.2 M) was added LiOH.H₂O (2equiv.) and the reaction mixture was stirred at room temperature for 2h. After completion, the solvents were evaporated under reduced pressureand the residue was acidified with saturated KHSO₄ solution andextracted with 10% methanol in chloroform. The aqueous layer wasevaporated under reduced pressure and stirred in 10% methanol inchloroform, filtered and concentrated under reduced pressure to affordthe intermediate. LC-MS: MS m/z 266 [M+H]⁺.

Step 4: Preparation ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-3-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide

¹H NMR (400 MHz, DMSO-d₆): 11.84 (s, 1H), 7.91 (s, 1H), 7.83 (d, J=7 Hz,1H), 7.57-7.49 (m, 2H), 6.77 (s, 1H), 6.35 (bs, 1H), 4.06-4.03 (t, J=5.7Hz, 2H), 3.96-3.92 (m, 2H), 2.89-2.86 (m, 1H), 2.60-2.55 (dd, J=4.8 Hz,16.7 Hz, 1H), 2.13-2.07 (bs, 5H), 1.13 (d, J=6.6 Hz, 3H). MS (ESI) m/z428.20 [M+H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 133

¹H NMR (400 MHz, DMSO-d₆): 11.86 (s, 1H), 7.90 (s, 1H), 7.83-7.82 (d,J=6.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.29 (br s, 1H), 6.78 (s, 1H), 6.54(br s, 1H), 4.14-4.11 (t, J=5.6 Hz, 2H), 3.92-3.90 (s, 2H), 2.95-2.91(m, 2H), 2.74-2.71 (t, J=6 Hz, 2H), 2.16-2.12 (m, 2H). LC-MS: MS m/z400.1 [M+H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-oxo-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)butanamide,Compound 134

¹H NMR (400 MHz, DMSO-d₆): 11.88 (s, 1H), 7.90 (s, 1H), 7.82 (d, J=7.6Hz, 1H), 7.58-7.51 (m, 2H), 6.89 (brs, 1H), 6.77 (s, 1H), 4.22 (t, J=5.6Hz, 2H), 3.95 (brs, 2H), 2.96 (m, 2H), 2.74 (t, J=6 Hz, 2H), 2.19 (brs,2H). LC-MS: MS m/z 467 [M-H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(2-methoxy-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 135

¹H NMR (400 MHz, DMSO-d₆): 7.87 (s, 1H), 7.79 (d, J=6.8 Hz, 1H),7.56-7.50 (m, 2H), 6.70 (s, 1H), 5.96 (b s, 1H), 3.93 (t, J=6.2 Hz, 2H),3.85 (b s, 2H), 3.71 (s, 3H), 2.90-2.88 (m, 2H), 2.67 (b s, 2H), 2.11 (bs, 2H). LC-MS: m/z 430 [M+H]⁺.

Synthesis of methyl4-(4-(3-(3-chlorophenyl)isoxazol-5-ylamino)-4-oxobutanoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylate,Compound 136

¹H NMR (400 MHz, DMSO-d₆): 9.3 (brs, 1H), 7.78 (s, 1H), 7.65 (d, J=7.2Hz, 1H), 7.41-7.34 (m, 2H), 6.63 (s, 1H), 4.31 (t, J=6.4 Hz, 2H), 3.96(brs, 2H), 3.92 (s, 3H), 3.03 (brs, 2H), 2.90 (brs, 2H), 2.28 (brs, 2H).

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(2-ethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 137

¹H NMR (400 MHz, Chloroform-d) 7.77 (1H, bs), 7.64 (1H, d, J=8.0 Hz),7.33-7.40 (2H, m), 7.25 (1H, s), 6.64 (1H, s), 4.18 (2H, t), 4.00 (2H,m), 2.90 (2H, m), 2.88 (2H, m,), 2.60 (2H, t), 2.19 (2H, m), 0.88 (3H,m).

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(6-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)-4-oxobutanamide,Compound 138 Step 1: Preparation of6-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole

To a stirred solution of 3-methyl-1H-pyrazol-5-amine (1 equiv.) in1,4-dioxane (0.5 M) was added triethylamine (5 equiv.) at roomtemperature. After 15 minutes, 1,2-dibromoethane (1.2 equiv.) was addedto the reaction mixture at room temperature. The reaction mixture wasstirred at 110° C. for 16 h. After completion, the reaction mixture wasfiltered and washed with ethyl acetate. The filtrate was concentratedunder reduced pressure to give crude product. The crude product waspurified by column chromatography to afford the product as an off-whitesolid. LC-MS: m/z 124 [M+H]⁺.

Step 2: Preparation of4-(6-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)-4-oxobutanoicacid

To a stirred solution of 6-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole(1 equiv.) in chloroform (0.5 M) was added dihydrofuran-2,5-dione (1.3equiv.). The reaction mixture was stirred at room temperature for 12 h.After completion, the solid thus precipitated was filtered and washedwith n-pentane and dried to afford the product as an off-white solid.LC-MS: m/z 224 [M+H]⁺.

Step 3: Preparation ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-4-(6-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)-4-oxobutanamide

¹H NMR (400 MHz, DMSO-d₆): 11.81 (brs, 1H), 7.89 (s, 1H), 7.82 (d, J=7.0Hz, 1H), 7.57-7.54 (m, 2H), 6.77 (s, 1H), 5.71 (s, 1H), 4.55 (t, J=7.8Hz, 1H), 4.32-4.24 (m, 2H), 4.20-4.16 (m, 1H), 2.84 (d, J=6.1 Hz, 1H),2.75 (s, 3H), 2.15 (s, 2H), 2.11 (s, 1H). LC-MS: m/z 400.22 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridazin-3-yl)butanamide,Compound 139 Step 1: Preparation of 2-methylpropane-1,3-diyldimethanesulfonate

To a stirred solution of 2-methylpropane-1,3-diol (1 equiv.) indichloromethane (0.45 M) was added methane sulfonyl chloride (2.7equiv.), using triethylamine (2.7 equiv.) at 0° C. to room temperaturefor 16 h. Upon completion of reaction, the reaction mixture was washedwith water and brine solution, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to the product as a brown solid.

Step 2: Preparation of2,6-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

To a stirred solution of 2-methylpropane-1,3-diyl dimethanesulfonate(1.2 equiv.) in 1,4-dioxane (0.5 M) were added3-methyl-M-pyrazol-5-amine (1 equiv.) and triethylamine (5 equiv.). Thereaction mixture was heated at 100° C. for 48 h. Upon completion ofreaction, the reaction mixture was filtered and concentrated underreduced pressure, purified by column chromatography to afford theproduct as a brown solid. LC-MS: m/z 152 [M+H]⁺.

Step 3: Preparation of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanoicacid

To a stirred solution of2,6-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1 equiv.) inchloroform (0.1 M) was added succinic anhydride (1 equiv.) and thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was concentrated under reduced pressure to afford the product asan off-white solid. LC-MS: m/z 252 [M+H]⁺.

Step 4: Preparation of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridazin-3-yl)butanamide

¹H NMR (400 MHz, DMSO-d₆): 8.37 (d, J=9.2 Hz, 1H), 8.23-8.17 (m, 1H),8.09 (d, J=7.2 Hz, 2H), 7.60-7.47 (m, 5H), 4.32-3.97 (m, 3H), 3.65-3.60(m, 1H), 2.95-2.75 (bs, 4H), 2.08 (s, 3H), 1.46 (s, 1H), 1.05 (s, 3H);LC-MS: m/z 405.0 [M+H]⁺.

Synthesis ofN-(2,3′-bipyridin-5-yl)-4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 140

¹H NMR (400 MHz, DMSO-d₆): 10.40 (s, 1H), 9.22 (d, J=2.0 Hz, 1H), 8.86(d, J=2.0 Hz, 1H), 8.62-8.57 (m, 1H), 8.40-8.35 (m, 1H), 8.20-8.15 (m,1H), 8.05-7.99 (m, 1H), 7.52-7.47 (m, 1H), 6.35 (bs, 1H), 4.15-4.00 (m,2H), 3.67-3.60 (m, 1H), 3.50-3.35 (m, 1H), 3.02-2.80 (m, 2H), 2.75-2.65(m, 2H), 2.35-2.20 (m, 1H), 2.08 (bs, 3H), 1.05 (d, J=4.4 Hz, 3H). MS(ESI) m/z 405 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyridin-3-yl)pyridazin-3-yl)butanamide,Compound 141

¹H NMR (400 MHz, DMSO-d₆): 11.33 (s, 1H), 9.27 (d, J=1.6 Hz, 1H), 8.69(dd, J=4.8, 1.6 Hz, 1H), 8.50-8.43 (m, 1H), 8.43-8.37 (m, 1H), 8.34-8.19(m, 1H), 7.70-7.55 (m, 1H), 6.35 (bs, 1H), 4.18-4.00 (m, 2H), 3.67-3.60(m, 1H), 3.50-3.35 (m, 1H), 3.02-2.85 (m, 2H), 2.85-2.78 (m, 2H),2.35-2.20 (m, 1H), 2.08 (bs, 3H), 1.05 (d, J=5.6 Hz, 3H). MS (ESI) m/z406 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide,Compound 142

¹H NMR (400 MHz, DMSO-d₆): 10.69 (s, 1H), 8.74-8.70 (m, 2H), 8.42-8.42(m, 1H), 8.16-8.14 (m, 2H), 7.97 (s, 1H), 6.34 (br, 1H), 4.14-4.04 (m,2H), 3.66-3.60 (q, 1H), 2.97-2.87 (m, 2H), 2.76-2.73 (m, 2H), 2.37 (s,3H), 2.08 (s, 3H), 1.06-1.04 (m, 3H). LC-MS: m/z 419 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(6-methyl-[2,3′-bipyridin]-6′-yl)-4-oxobutanamide,Compound 143

¹H NMR (400 MHz, DMSO-d₆): 10.71 (s, 1H), 9.01-9.00 (m, 1H), 8.42-8.40(m, 1H), 8.17-8.15 (d, J=8.8 Hz, 1H), 7.80-7.75 (m, 2H), 7.23-7.21 (m,1H), 6.33 (br, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.86 (br, 2H), 2.89-2.87 (m,2H), 2.75-2.72 (m, 2H), 2.54 (s, 3H), 2.08 (br, 5H). LC-MS: m/z 405[M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[2,3′-bipyridin]-5-yl)-4-oxobutanamide,Compound 144

¹H NMR (400 MHz, DMSO-d₆): 10.39 (s, 1H), 9.01 (m, 1H), 8.85 (br, 1H),8.43-8.42 (m, 1H), 8.21 (br, 1H), 8.18-8.15 (m, 1H), 8.00 (d, J=8.8 Hz,1H), 6.33 (br, 1H), 4.14-4.10 (m, 2H), 3.66-3.61 (m, 1H), 2.99-2.89 (m,2H), 2.72-2.67 (m, 2H), 2.38 (s, 3H), 2.08 (s, 3H), 1.06-1.05 (m, 3H).LC-MS: m/z 419 [M+H]⁺.

Synthesis ofN-([2,3′-bipyridin]-5-yl)-2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 145

¹H NMR (400 MHz, DMSO-d₆): 10.38 (s, 1H), 9.22 (d, J=1.6 Hz, 1H), 8.88(d, J=2.4 Hz, 1H), 8.59 (dd, J=4.8, 1.6 Hz, 1H), 8.38 (dt, J=8.0, 2.0Hz, 1H), 8.22-8.18 (m, 1H), 8.03-8.00 (m, 1H), 7.53-7.48 (m, 1H), 6.35(bs, 1H), 4.05-4.00 (m, 2H), 3.90-3.84 (m, 2H), 3.10-3.00 (m, 2H),2.75-2.60 (m, 1H), 2.07 (bs, 5H), 1.21 (d, J=6.4 Hz, 3H). MS (ESI) m/z405 [M+H]⁺.

Synthesis ofN-([3,3′-bipyridin]-6-yl)-2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 147

¹H NMR (400 MHz, DMSO-d₆): 10.68 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H),8.58-8.57 (m, 1H), 8.19-8.12 (m, 3H), 7.51-7.48 (m, 1H), 6.27 (br, 1H),4.02 (t, J=6.0 Hz, 2H), 3.86 (br, 2H), 3.06-2.99 (m, 1H), 2.06 (br, 5H),1.19 (d, J=7.2 Hz, 3H). LC-MS: m/z 405 [M+H]⁺.

Synthesis ofN-(4-methyl-2,3′-bipyridin-6′-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 148

¹H NMR (400 MHz, DMSO-d₆): 10.70 (s, 1H), 9.01 (d, J=2.1 Hz, 1H), 8.51(d, J=4.8 Hz, 1H), 8.43-8.40 (dd, J=2.6 Hz, 8.7 Hz, 1H), 8.15 (d, J=8.8Hz, 1H), 7.85 (s, 1H), 7.19 (d, J=4.8 Hz, 1H), 6.33 (brs, 1H), 4.02 (t,J=5.7 Hz, 2H), 3.86 (brs, 2H), 2.89 (t, J=5.7 Hz, 2H), 2.74 (t, J=6.1Hz, 2H), 2.39 (s, 3H), 2.08 (brs, 5H); MS (ESI) m/z 405.18 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-(5-methylpyrazin-2-yl)pyridin-2-yl)-4-oxobutanamide,Compound 149

¹H NMR (400 MHz, DMSO-d₆): 10.75 (s, 1H), 9.14 (d, J=0.8 Hz, 1H), 9.04(d, J=2.2 Hz, 1H), 8.60 (s, 1H), 8.46-8.43 (dd, J=2.2 Hz, 2.2 Hz, 1H),8.19 (d, J=8.7 Hz, 1H), 6.33 (brs, 1H), 4.02 (t, J=5.7 Hz, 2H), 3.86(brs, 2H), 2.89 (t, J=6.1 Hz, 2H), 2.75 (t, J=6.6 Hz, 2H), 2.53 (s, 3H),2.07 (brs, 5H). MS (ESI) m/z 406.16 [M+H]⁺.

Synthesis of2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[2,3′-bipyridin]-5-yl)-4-oxobutanamide,Compound 150

¹H NMR (400 MHz, DMSO-d₆): 10.37 (s, 1H), 9.01 (s, 1H), 8.87 (s, 1H),8.42 (s, 1H), 8.21-8.17 (m, 2H), 7.99 (d, J=8.8 Hz, 1H), 6.32 (br, 1H),4.03-4.00 (m, 2H), 3.86 (br, 2H), 3.04-3.01 (m, 2H), 2.69-2.66 (m, 1H),2.38 (s, 3H), 2.07 (br, 5H), 1.21 (d, J=6.0 Hz, 3H). LC-MS: m/z 419[M+H]⁺.

Synthesis of2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyrazin-2-yl)pyridin-2-yl)-4-oxobutanamide,Compound 151

¹H NMR (400 MHz, DMSO-d₆): 10.78 (s, 1H), 9.08 (s, 2H), 8.56-8.46 (m,2H), 8.21 (d, J=8.4 Hz, 1H), 6.29 (br, 1H), 4.02 (m, 2H), 3.86 (br, 2H),3.18 (br, 2H), 3.05-2.99 (m, 1H), 2.57 (s, 3H), 2.06 (br, 5H), 1.19 (d,J=6.8 Hz, 3H). LC-MS: m/z 420 [M+H]⁺.

Synthesis of2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide,Compound 152

¹H NMR (400 MHz, DMSO-d₆): 10.67 (s, 1H), 8.75-8.69 (m, 2H), 8.42 (s,1H), 8.20-8.10 (m, 2H), 7.96 (s, 1H), 6.35 (bs, 1H), 4.05-4.00 (m, 2H),3.90-3.80 (m, 2H), 3.20-3.10 (m, 2H), 3.10-2.95 (m, 1H), 2.37 (s, 3H),2.07 (bs, 5H), 1.19 (d, J=6.8 Hz, 3H). MS (ESI) m/z 419 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyrimidin-5-yl)pyridin-2-yl)butanamide,Compound 153

¹H NMR (400 MHz, DMSO-d₆): 10.73 (s, 1H), 9.19 (d, J=2.2 Hz, 3H), 8.79(d, J=2.2 Hz, 1H), 8.25-8.18 (m, 2H), 6.32 (brs, 1H), 4.03 (t, J=5.7 Hz,2H), 3.86 (s, 2H), 2.89 (t, J=6.2 Hz, 2H), 2.75 (t, J=6.6 Hz, 2H), 2.08(s, 5H). MS (ESI) m/z 392.15 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyrimidin-5-yl)pyridin-3-yl)butanamide,Compound 154

¹H NMR (400 MHz, DMSO-d₆): 10.44 (s, 1H), 9.39 (s, 2H), 9.20 (s, 1H),8.89 (s, 1H), 8.22-8.20 (dd, J=2.2 Hz, 8.8 Hz, 1H), 8.10 (d, J=8.4 Hz,1H), 6.33 (brs, 1H), 4.02 (t, J=5.7 Hz, 2H), 3.86 (s, 2H), 2.90 (d,J=6.2 Hz, 2H), 2.71 (t, J=6.2 Hz, 2H), 2.08 (s, 5H). MS (ESI) m/z 392.15[M+H]⁺.

Synthesis ofN-(5-fluoro-6-phenylpyridin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 156

¹H NMR (400 MHz, DMSO-d₆): 10.62 (s, 1H), 8.64 (s, 1H), 8.15 (dd,J=13.6, 2.0Hz, 1H), 7.92-7.85 (m, 2H), 7.55-7.56 (m, 2H), 7.56-7.40 (m,1H), 6.35 (bs, 1H), 4.03 (t, J=5.6 Hz, 2H), 3.87 (bs, 2H), 2.95-2.85 (m,2H), 2.75-2.65 (m, 2H), 2.08 (bs, 5H); MS (ESI) m/z 408 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyrazin-2-yl)pyridin-2-yl)-4-oxobutanamide,Compound 157

¹H NMR (400 MHz, DMSO-d₆): 10.80 (s, 1H), 9.08-9.07 (m, 2H), 8.54-8.47(m, 2H), 8.21-8.19 (m, 1H), 6.34 (br, 1H), 4.13-4.04 (m, 3H), 3.66-3.61(m, 2H), 2.95-2.86 (m, 2H), 2.77-2.75 (m, 2H), 2.57 (s, 3H), 2.08 (s,3H), 1.06-1.05 (m, 3H). LC-MS: m/z 420 [M+H]⁺.

Synthesis ofN-(3-fluoro-5′-methyl-[2,3′-bipyridin]-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 158

¹H NMR (400 MHz, DMSO-d₆): 10.69 (s, 1H), 8.85 (s, 1H), 8.67 (s, 1H),8.47 (m, 1H), 8.20-8.17 (m, 1H), 8.07 (s, 1H), 6.32 (br, 1H), 4.03 (t,J=5.6 Hz, 2H), 3.87 (br, 2H), 2.93-2.90 (m, 2H), 2.73-2.70 (m, 2H), 2.38(s, 3H), 2.08 (br, 5H). LC-MS: m/z 423 [M+H]⁺.

Synthesis ofN-(3-(3-chlorophenyl)isoxazol-5-yl)-2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 159

¹H NMR (400 MHz, DMSO-d₆): 11.86 (br, 1H), 7.84-7.77 (m, 2H), 7.53-7.51(m, 2H), 6.66 (br, 1H), 6.34 (br, 1H), 4.03-4.00 (m, 2H), 3.84 (br, 2H),3.07-2.95 (m, 2H), 2.07 (br, 5H), 1.74 (br, 1H), 1.18-1.16 (d, J=4.8 Hz,3H). LC-MS: m/z 428 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4-methyl-2,3′-bipyridin-6′-yl)-4-oxobutanamide,Compound 160 and Compound 161

The product was subjected to chiral chromatography to affordenantiomeric pure compound 160 and compound 161.

¹H NMR (400 MHz, DMSO-d₆): 10.66 (s, 1H), 8.73 (s, 1H), 8.69 (s, 1H),8.42 (s, 1H), 8.17-8.14 (m, 2H), 7.95 (s, 1H), 6.33 (brs, 1H), 4.14-4.07(m, 2H), 3.65-3.60 (dd, J=9.2 Hz, 11.8 Hz 1H), 3.4 (s, 1H) 2.97-2.86 (m,2H), 2.74 (t, J=6.1 Hz, 2H), 2.37 (s, 3H), 2.32-2.28 (m, 1H), 2.08 (brs,3H), 1.05 (d, J=5.7 Hz, 3H). MS (ESI) m/z 419.15 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′-fluoro-[2,3′-bipyridin]-5-yl)-4-oxobutanamide,Compound 162

¹H NMR (400 MHz, DMSO-d₆): 10.46(s, 1H), 9.13 (s, 1H), 8.88 (br, 1H),8.60-8.59 (m, 1H), 8.30-8.26 (m, 1H), 8.21-8.18 (m, 1H), 8.11-8.08 (m,1H), 6.34 (br, 1H), 4.13-4.04 (m, 2H), 3.66-3.61 (m, 1H), 3.36 (br, 1H),3.00-2.80 (m, 2H), 2.73-2.66 (m, 2H), 2.28 (br, 1H), 2.08 (s, 3H),1.06-1.05 (m, 3H). LC-MS: m/z 423 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′-fluoro-[3,3′-bipyridin]-6-yl)-4-oxobutanamide,Compound 163

¹H NMR (400 MHz, DMSO-d₆): 10.74 (s, 1H), 8.86 (s, 1H), 8.79-8.78 (m,1H), 8.59-8.58 (m, 1H), 8.24-8.21 (m, 1H), 8.18-8.14 (m, 2H), 6.34 (br,1H), 4.13-4.05 (m, 2H), 3.66-3.60 (m, 1H), 3.40 (br, 1H), 2.95-2.86 (m,2H), 2.76-2.73 (m, 2H), 2.28 (br, 1H), 2.08 (s, 3H), 1.06-1.04 (m, 3H).LC-MS: m/z 423 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-fluoro-[2,3′-bipyridin]-6′-yl)-4-oxobutanamide,Compound 164

¹H NMR (400 MHz, DMSO-d₆): 10.73 (s, 1H), 8.99 (d, J=2.0 Hz, 1H), 8.66(d, J=2.8 Hz, 1H), 8.42-8.38 (m, 1H), 8.20-8.12 (m, 1H), 8.12-8.06 (m,1H), 7.89-7.80 (m, 1H), 6.33 (bs, 1H), 4.15-4.00 (m, 2H), 3.67-3.60 (m,1H), 3.55-3.35 (m, 1H), 3.00-2.80 (m, 2H), 2.80-2.70 (m, 2H), 2.30-2.20(m, 1H), 2.08 (bs, 3H), 1.05 (d, J=5.6 Hz, 3H). MS (ESI) m/z 423 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(4-fluoro-[3,3′-bipyridin]-6-yl)-4-oxobutanamide,Compound 165

¹H NMR (400 MHz, DMSO-d₆): 10.99 (s, 1H), 8.80 (s, 1H), 8.65-8.55 (m,2H), 8.06-7.98 (m, 2H), 7.56-7.50 (m, 1H), 6.33 (bs, 1H), 4.15-4.00 (m,2H), 3.67-3.60 (m, 1H), 3.50-3.35 (m, 1H), 3.00-2.80 (m, 2H), 2.80-2.70(m, 2H), 2.35-2.20 (m, 1H), 2.08 (bs, 3H), 1.05 (d, J=4.8 Hz, 3H). MS(ESI) m/z 423 [M+H]⁺.

Synthesis ofN-(3,5′-dimethyl-[2,3′-bipyridin]-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 168

¹H NMR (400 MHz, DMSO-d₆): 10.29 (s, 1H), 8.68 (s, 1H), 8.53 (d, J=2.0Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.76 (s, 1H),6.35 (bs, 1H), 4.03 (t, J=5.6 Hz, 2H), 3.87 (bs, 2H), 2.95-2.85 (m, 2H),2.72-2.65 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.08 (bs, 5H); MS (ESI)m/z 419 [M+H]⁺.

Synthesis ofN-(3,3′-bipyridin-6-yl)-4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 169 and Compound 170

The product was subjected to chiral chromatography to affordenantiomeric pure compound 169 and compound 170.

¹H NMR (400 MHz, DMSO-d₆): 10.67 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.71(s, 1H), 8.58 (d, J=4.0 Hz, 1H), 8.16-8.11 (m, 3H), 7.50-7.47 (dd, J=4.4Hz, 7.6 Hz, 1H), 6.3 (brs, 1H), 4.14-4.06 (m, 2H), 3.65-3.60 (m, 1H),3.4 (s, 1H), 2.97-2.87 (m, 2H), 2.75 (t, J=12.8 Hz, 2H), 2.30 (d, J=14.8Hz, 1H), 2.08 (s, 3H), 1.05 (d, J=6.4 Hz, 3H); MS (ESI) m/z 405.18[M+H]⁺.

Synthesis ofN-([2,3′-bipyridin]-6′-yl)-4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 171

¹H NMR (400 MHz, DMSO-d₆): 10.72 (s, 1H), 9.03 (m, 1H), 8.67-8.66 (m,1H), 8.45-8.42 (m, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.01-7.99 (m, 1H),7.91-7.87 (m, 1H), 7.38-7.35 (m, 1H), 6.34 (br, 1H), 4.14-4.06 (m, 2H),3.66-3.60 (m, 1H), 2.97-2.86 (m, 2H), 2.76-2.73 (m, 2H), 2.29 (br, 1H),2.08 (s, 3H), 1.05 (m, 3H). MS (ESI) m/z 405 [M+H]⁺.

Amide Coupling Method B:

Triethylamine (1.3 eq) and isobutyl chloroformate (1.0 equiv.) wereadded dropwise to a stirred solution of acid (1.1 equiv.) indichloromethane (0.05 M) at 0° C. and stirred for 15 minutes beforeadding the respective amine (1.0 equiv.). The reaction was stirred from0° C. to room temperature for 3 hours. Upon completion the reaction wasdiluted with dichloromethane and basified to pH 9.0 with saturatedsodium carbonate solution. The aqueous layer was extracted withdichloromethane, organic phase combined, washed with brine, dried oversodium sulphate, filtered and concentrated in vacuo. Crude was purifiedwith reversed phase HPLC to afford the pure product.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyridin-3-yl)pyridazin-3-yl)butanamide,Compound 51

¹H NMR (400 MHz, DMSO-d₆): 11.32 (S, 1H), 9.26 (d, J=2 Hz, 1H),8.70-8.68 (m, 1H), 8.48-8.46 (m, 1H), 8.40 (d, J=9.2 Hz, 1H), 8.30 (d,J=9.6 Hz, 1H), 7.59-7.56 (m, 1H), 6.33 (bs, 1H), 4.02 (t, J=5.8 Hz, 2H),3.86 (bs, 2H), 2.91-2.90 (m, 2H), 2.83-2.80 (m, 2H), 2.08 (bs, 5H).LC-MS: m/z 392 [M+H]⁺.

Synthesis ofN-(6-(3-fluorophenyl)pyridin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 84

¹H NMR (400 MHz, DMSO-d₆): 10.73 (s, 1H), 8.83 (d, J=2.4 Hz, 1H),8.16-8.14 (m, 1H), 7.99-7.97 (m, 1H), 7.90-7.88 (m, 1H), 7.85-7.82 (m,1H), 7.53-7.47 (m, 1H), 7.24-7.19 (m, 1H), 6.34 (br s, 1H), 4.02 (t,J=6.0 Hz, 2H), 3.87 (s, 2H), 2.92-2.89 (m, 2H), 2.71-2.68 (m, 2H), 2.08(s, 5H). LC-MS: m/z 408 [M+H]⁺.

Synthesis ofN-(6-(3-fluorophenyl)pyridazin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 98

¹H NMR (400 MHz, DMSO-d₆): 11.30 (s, 1H), 8.39-8.37 (m, 1H), 8.28-8.26(m, 1H), 7.97-7.91 (m, 2H), 7.61-7.56 (m, 1H), 7.36-7.31 (m, 1H), 6.34(br s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.86 (s, 2H), 2.91-2.90 (m, 2H),2.82-2.79 (m, 2H), 2.08 (s, 5H). LC-MS: m/z 409 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(6-(5-methylpyridin-3-yl)pyridazin-3-yl)-4-oxobutanamide,Compound 104

¹H NMR (400 MHz, DMSO-d₆): 11.31 (s, 1H), 9.06 (s, 1H), 8.53 (s, 1H),8.40-8.38 (m, 1H), 8.30-8.27 (m, 2H), 6.33 (br s, 1H), 4.02 (t, J=6.0Hz, 2H), 3.86 (s, 2H), 2.91-2.90 (m, 2H), 2.82-2.79 (m, 2H), 2.41 (s,3H), 2.08 (s, 5H). LC-MS: m/z 406 [M+H]⁺.

Amide Coupling Method C:

Amine (1.1 equiv.) was added to a stirred solution of acid,N,N-diisopropylethylamine (3.0 equiv.) and HATU (1.5 equiv.) in DMF (0.2M) after 5 minutes. Solution is left to stir at room temperature for 3h. Upon completion the reaction was diluted with water and extractedwith dichloromethane. The organic phase was combined, washed with brine,dried over sodium sulphate, filtered and concentrated in vacuo. Crudewas purified by Shimadzu semi-prep and lyophilized to afford a whitesolid.

Synthesis ofN-(2′-fluoro-[1,1′-biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 64

¹H NMR (400 MHz, DMSO-d₆): 10.14 (s, 1H), 7.70 (d, J=8.4 Hz, 2H),7.53-7.48 (m, 3H), 7.39-7.35 (m, 1H), 7.31-7.26 (m, 2H), 6.35 (br, 1H),4.02 (t, J=6.0 Hz, 2H), 3.87 (br, 2H), 2.91-2.88 (m, 2H), 2.68-2.65 (m,2H), 2.08 (br, 5H). LC-MS: m/z 407 [M+H]⁺.

Synthesis ofN,N-dimethyl-4′-(4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamido)-[1,1′-biphenyl]-3-carboxamide,Compound 68

¹H NMR (400 MHz, DMSO-d₆): 10.11 (s, 1H), 7.72-7.62 (m, 6H), 7.49 (t,J=7.6 Hz, 1H), 7.34-7.32 (m, 1H), 6.33 (bs, 1H), 4.02 (t, J=6.0 Hz, 2H),3.87 (bs, 2H), 2.97 (d, J=23.6 Hz, 6H), 2.91-2.87 (m, 2H), 2.68-2.65 (m,2H), 2.08 (bs, 5H). LC-MS: m/z 460 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(3′-morpholinobiphenyl-4-yl)-4-oxobutanamide,Compound 73

¹H NMR (400 MHz, DMSO-d₆): 10.05 (s, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.59(d, J=8.8 Hz, 2H), 7.27 (t, J=8.0 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J=7.6Hz, 1H), 6.90 (d, J=6.4 Hz, 1H), 6.32 (bs, 1H), 4.02 (t, J=6.4 Hz, 2H),3.86 (bs, 2H), 3.75 (t, J=4.8 Hz, 4H), 3.17 (t, J=4.8 Hz, 4H), 2.88 (t,J=6.4 Hz, 2H), 2.65 (t, J=6.4 Hz, 2H), 2.08 (bs, 5H). MS (ESI) m/z474.33 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(1-phenylpiperidin-4-yl)butanamide,Compound 81

¹H NMR (400 MHz, DMSO-d₆): 7.82 (d, J=7.6 Hz, 1H), 7.18 (t, J=6.8 Hz,2H), 6.92 (d, J=8.0 Hz, 2H), 6.73 (t, J=7.6 Hz, 1H), 6.20 (s, 1H), 4.00(t, J=6.0 Hz, 2H), 3.82 (s, 2H), 3.80-3.61 (m, 3H), 2.80-2.74 (m, 4H),2.38 (t, J=6.8 Hz, 2H), 2.08 (bs, 5H), 1.79 (d, J=9.6 Hz, 2H), 1.55-1.44(m, 2H). MS (ESI) m/z 396.40 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(m-tolyl)pyridazin-3-yl)butanamide,Compound 99

¹H NMR (400 MHz, DMSO-d₆): 11.25 (s, 1H), 8.35 (d, J=9.6 Hz, 1H), 8.19(d, J=9.6 Hz, 1H), 7.93 (bs, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.6Hz, 1H), 7.32-7.30 (m, 1H), 6.30 (bs, 1H), 4.04-4.01 (t, J=5.8 Hz, 2H),3.87 (bs, 2H), 2.91-2.90 (m, 2H), 2.82-2.79 (m, 2H), 2.41 (s, 3H), 2.08(bs, 5H). LC-MS: m/z 405 [M+H]⁺.

Synthesis ofN-(6-(5-fluoropyridin-3-yl)pyridazin-3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 103

¹H NMR (400 MHz, DMSO-d₆): 11.38 (s, 1H), 9.18 (s, 1H), 8.71 (d, J=2.8Hz, 1H), 7.45-7.33 (m, 3H), 6.34 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87(bs, 2H), 2.95-2.85 (m, 2H), 2.85-2.75 (m, 2H), 2.08 (bs, 5H). MS (ESI)m/z 410 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(5-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)butanamide,Compound 105

¹H NMR (400 MHz, DMSO-d₆): 11.41 (s, 1H), 9.58 (m, 1H), 9.10 (m, 1H),8.83 (m, 1H), 8.46 (m, 2H), 6.33 (bs, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.87(bs, 2H), 2.93-2.91 (m, 2H), 2.84-2.81 (m, 2H), 2.08 (bs, 5H). LC-MS:m/z 460 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5-methyl-6-(pyridin-3-yl)pyridazin-3-yl)-4-oxobutanamide,Compound 106

¹H NMR (400 MHz, DMSO-d₆): 11.21 (s, 1H), 8.81-8.80 (m, 1H), 8.69-8.68(m, 1H), 8.28 (s, 1H), 8.07-8.04 (m, 1H), 7.57-7.54 (m, 1H), 6.33 (s,1H), 4.03 (t, J=5.8 Hz, 2H), 3.87 (bs, 2H), 2.93-2.89 (m, 2H), 2.81-2.78(m, 2H), 2.34 (s, 3H), 2.08 (bs, 5H). LC-MS: m/z 406 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(6-(6-methylpyridin-3-yl)pyridazin-3-yl)-4-oxobutanamide,Compound 107

¹H NMR (400 MHz, DMSO-d₆): 11.29 (s, 1H), 9.14-9.13(m, 1H), 8.39-8.34(m, 2H), 8.28-8.25 (m, 1H), 7.42 (d, J=8.0 Hz, 1H), 6.33 (bs, 1H), 4.03(t, J=6.0 Hz, 2H), 3.87 (bs, 2H), 2.93-2.90 (m, 2H), 2.82-2.79 (m, 2H),2.55 (s, 3H), 2.08 (bs, 5H). LC-MS: m/z 406 [M+H]⁺.

Synthesis ofN-(5′-methyl-2,3′-bipyridin-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 110

¹H NMR (400 MHz, DMSO-d₆): 10.35 (s, 1H), 9.01 (s, 1H), 8.85 (d, J=2.0Hz, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 8.16 (d, J=10.8 Hz, 1H), 7.99 (d,J=8.8 Hz, 1H), 6.34 (s, 1H), 4.02 (t, J=5.6 Hz, 2H), 3.86 (bs, 2H),2.93-2.88 (m, 2H), 2.73-2.67 (m, 2H), 2.37 (s, 3H), 2.08 (bs, 5H). MS(ESI) m/z 405.33 [M+H]⁺.

Synthesis of2-methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridazin-3-yl)butanamide,Compound 146

¹H NMR (400 MHz, DMSO-d₆): 11.25 (s, 1H), 8.37 (d, J=9.6 Hz, 1H), 8.21(d, J=9.6 Hz, 1H), 8.11-8.09 (m, 2H), 7.55-7.50 (m, 3H), 6.31 (s, 1H),4.02 (t, J=6.0 Hz, 2H), 3.86 (br, 2H), 3.25-3.21 (m, 1H), 3.07-3.00 (m,1H), 2.06 (br, 5H), 1.22 (d, J=7.2 Hz, 3H). LC-MS: m/z 405 [M+H]⁺.

Synthesis ofN-(2-fluorobiphenyl-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxobutanamide,Compound 155

¹H NMR (400 MHz, DMSO-d₆): 11.32 (s, 1H), 9.27 (d, J=2.0 Hz, 1H), 8.69(dd, J=4.8, 1.6 Hz, 1H), 8.47 (dt, J=8.4, 1.6 Hz, 1H), 8.45-8.38 (m,1H), 8.32-8.28 (m, 1H), 7.53-7.60 (m, 1H), 6.35 (bs, 1H), 4.05-4.00 (m,1H), 3.95-3.80 (m, 2H), 3.25-3.15 (m, 2H), 3.10-2.95 (m, 1H), 2.75-2.55(m, 1H), 2.06 (bs, 5H), 1.22 (d, J=7.2 Hz, 3H). MS (ESI) m/z 406 [M+H]⁺.

Synthesis of4-(2-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyrazin-2-yl)pyridin-3-yl)butanamide,Compound 166

¹H NMR (400 MHz, DMSO-d₆): 10.46 (s, 1H), 9.47 (d, J=1.6 Hz, 1H), 8.89(s, 1H), 8.70 (t, J=2.8 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.31-8.29 (m,1H), 8.26-8.23 (dd, J=2.4 Hz, 8.8 Hz,1H), 6.3 (brs, 1H), 4.06-4.01 (m,2H), 3.87 (brs, 1H), 3.17 (d, J=5.2 Hz, 1H), 2.92 (t, J=6.4 Hz, 2H),2.73-2.70 (t, J=6.4 Hz, 2H), 2.08 (s, 5H); MS (ESI) m/z 392.2 [M+H]⁺.

Synthesis of4-(2,6-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(6-(5-fluoropyridin-3-yl)pyridazin-3-yl)-4-oxobutanamide,Compound 167

¹H NMR (400 MHz, DMSO-d₆): 11.38 (s, 1H), 9.18 (s, 1H), 8.71 (d, J=2.8Hz, 1H), 8.55-8.45 (m, 3H), 6.34 (bs, 1H), 4.15-4.00 (m, 2H), 3.68-3.60(m, 1H), 3.45-3.30 (m, 1H), 3.00-2.85 (m, 2H), 2.85-2.80 (m, 2H),2.35-2.20 (m, 1H), 2.07 (bs, 3H), 1.05 (d, J=4.8 Hz, 3H); MS (ESI) m/z424 [M+H]⁺.

Materials and Methods

Cell Lines and Culture Conditions:

HEK293-STF cell line was modified from Human embryonic kidney cell lineHEK293 transfected with the STF reporter. HEK293-STF3A cell line wasfurther modified from HEK293-STF cell line to express Wnt3A. This cellline was used to identify compounds that regulate either early or latesignaling components of the Wnt pathway. These two cell lines wereobtained from David Virshup's laboratory, Duke-NUS. L-Wnt3A (ATCC,#CRL-2647) cell line was used for providing Wnt3A conditioned media. Thethree cell lines were grown in DMEM with 10% FBS incubated in 37° C.with 5% CO2.

Cell Viability Assay:

5000 cells in 75 μl culture media were seeded in each well of black 96well plates (Greiner #655090) and incubated overnight at 37° C. 25 μl ofserially diluted compound was added to the cells giving finalconcentration of 50 μM to 1.5 nM. After 1 day of treatment, 100 μl ofCellTiter-Glo Luminescent Cell Viability Assay reagent (#G7571, Promega)was added to each well and incubated for 10 minutes at room temperature.Luminescence was measured using Tecan Safire2 microplate reader.

STF3A Assay:

2×10⁴ HEK293-STF3A cells in 75 μl culture media were seeded in each wellof white 96 well plates (Greiner #655098) and incubated overnight at 37°C. 25 μl serially diluted compound was added to the cells to give finalconcentration of 50 μM to 1.5 nM. After 1 day of treatment, 100 μl ofSteady-Glo Luciferase Assay reagent (#E2520, Promega) was added to eachwell and incubated for 10 minutes at room temperature. Luminescence wasmeasured using Tecan Safire2 plate reader.

STF/WNT3A Conditioned Medium (STF/WNT3A CM) Assay:

L-Wnt3A cells were cultured in three T-175 flasks at 3×10⁴ cells/ml in30 ml culture medium per flask. After 4 days of incubation, the Wnt3Aconditioned media were harvested and then centrifuged at 2000 rpm for 10minutes to remove the debris. The Wnt3A conditioned media were stored at−20° C. if not used immediately.

2×10⁴ HEK293-STF cells in 25 μl culture media were added in each well ofwhite 96 well plates (Greiner #655098). 25 μl serially diluted compoundwas added to the cells. After 4 hours of incubation, 100 μl Wnt-3Aconditioned medium was added to the cells. The final concentration ofcompound ranged from 33 μM to 1 nM. After incubation for 1 day at 37°C., 100 μl of Steady-Glo® Luciferase Assay reagent (#E2520, Promega) wasadded to each well and incubated for 10 minutes at room temperature.Luminescence was measured using Tecan Safire2 microplate reader.

Western Blot:

8.0×10⁵ cells in 2.5 ml media were seeded in T-25 flasks. Compounds werediluted to 600 nM in 1 ml medium and 0.5 ml was added to the T-25 flaskto give a final concentration of 100 nM. After incubation in 37° C. fortwo days, the culture media were collected and centrifuged at 2000 rpmfor 10 min. The supernatants were collected and 32 μl from each samplewas used for SDS PAGE gel electrophoresis. After transferring theseparated proteins to the membrane it was incubated with the primaryWnt3A antibody (1:1000, #09-162, Millipore) overnight. After washingwith Tris-Buffered Saline containing 0.05% Tween 20 (TBST), the membranewas incubated with polyclonal Goat anti-Rabbit IgG HRP-conjugatedsecondary antibody (1:3000, #P0448) for 1 hour at room temperature.After washing with TBST, the membrane was developed with Amersham™ ECL™Select Western Blotting Detection Reagent (#RPN2235, GE Healthcare LifeSciences) and documented with Bio-Rad Molecular Imager VersaDoc MP.

MMTV-Wnt1 Mouse Model 1:

8-10 weeks old Female BALBc mice were anesthetised with 150mg/kgKetamine +75mg/kg Xylazine. Under aseptic conditions, skin near the4^(th) mammary fat pad was incised. Mammary fat pad was tweaked withforceps and tumor fragment ˜2mm³ was implanted. The incision was closedusing a tissue adhesive. Animals were randomised into groups of eightand treated daily with the test compounds for 14 days. Tumors weremeasured in two dimensions using calipers, and volume was calculatedusing the formula: Tumor Volume (mm³)=w²×1/2. Maximum tumor volume limitwas 2000mm³.

Wnt3A Palmitoylation Assay:

The assay used to determine the inhibition of the palmitoylation of Wntsby compound was described by Yap et al, (Yap M C, Kostiuk M A, Martin DD, Perinpanayagam M A, Hak P G, Siddam A, Majjigapu J R, Rajaiah G,Keller B O, Prescher J A, Wu P, Bertozzi C R, Falck J R, Berthiaume L G.2010. Rapid and selective detection of fatty acylated proteins usingomega-alkynyl-fatty acids and click chemistry. J Lipid Res.51(6):1566-1580) with some modification. 3×10⁶ HeLa cells were seeded in10 cm culture dish and incubated at 37° C. overnight. The cells weretransfected with 5 μg pCDNA3.2/V5-Wnt3a vector (Najdi R, Proffitt K,Sprowl S, Kaur S, Yu J, Covey T M, Virshup D M, Waterman M L. 2012. Auniform human Wnt expression library reveals a shared secretory pathwayand unique signaling activities. Differentiation, 84(2), 203-213.doi:10.1016/j.diff.2012.06.004) to over-express VS-tagged Wnt3a. Aftersix hours, the cells were washed with PBS and treated with 100 μM alkynepalmitate in medium with 5% BSA. 100nM compound or DMSO was added andthe cells were incubated overnight at 37° C. The cells were lyzed and600 μg cell lysate was collected and incubated with anti-V5 antibody(Invitrogen) followed by the pull down of V5-Wnt3a with the addition ofProtein A/G agarose beads (Thermo scientific). The pulled down lysatescontaining V5-Wnt3a was click-reacted with biotin-azide (Invitrogen).The biotin-labelled protein lysate was then separated on SDS-PAGE andtransferred to a nitrocellulose membrane. The membrane was incubatedwith primary anti-V5 antibody, followed by secondary anti-mouse Dylight680 (Thermo scientific) to detect V5-Wnt3a. The membrane was thenincubated with streptavidin-Dylight 800 (Thermo scientific) to detectbiotin labelled Wnt3a. The signals were captured on the Odyssey CLxInfrared Imaging System (LI-COR Bioscience).

Soft Agar Assay:

AsPC-1 cells were maintained in RPMI164 supplemented with 10% FBS, 2 mML-glutamine and P/S (100 units/ml penicillin and 100 μg/mlstreptomycin). HPAF-II cells were maintained in MEM (Eagles')supplemented with 10% FBS, 2 mM L-glutamine and P/S (100 units/mlpenicillin and 100 μg/ml streptomycin). CFPAC-1 cells were maintained inIscove MEM supplemented with 10% FBS, 2 mM L-glutamine and P/S (100units/ml penicillin and 100 μg/m1 streptomycin).

600 μl of 0.6% agar was added to 24-well plate to form the base layer.Then a middle layer of 0.36% agar (containing 5000 cells and seriallydiluted compound) was added on to the base layer. Finally 500 μl offresh growth medium was added to the top of the middle layer. The plateswere incubated at 37° C. with 5% carbon dioxide in a humidifiedincubator for 2 weeks. Formation of colonies was observed using a lightmicroscope. When the colony size was larger than 500 μm, 70 μl MTT (5mg/ml) was added to each well and the plates were incubated at 37° C.for at least 2 hours. Colonies were counted with GelCount® instrument.The colony counts were plotted against compound concentrations using theGraphPad Prism software. The software was also used to performnon-linear curve fitting and calculation of compound concentration thatinhibited 50% colony formation.

Results:

Compounds of the present invention specifically inhibit mammalian PORCN.

PORCN-null HT1080 cells were transfected with mammalian or Xenopus PORCNexpression plasmids, along with WNT3A, STF reporter and mCherry astransfection control. 6 hours after transfection, cells were treatedwith the compounds or DMSO as indicated, and the following day assayedfor luciferase. Xenopus PORCN was resistant to the inhibitory effects ofcompounds. The two compounds, Compound 51 and Compound 110 inhibit theactivity of mammalian porcupine (FIG. 1).

Treatment with Compounds 51 and 110 decreased tumor growth in all thetreated mice (FIG. 2 and FIG. 3).

Palmitoylation of Wnt3a is inhibited by Compound 51 (FIG. 4). TheWnt3a-V5 was visualized using anti-V5 antibody, followed by anti-mouseDylight 680. B. Biotin-azide clicked palmitate in V5-Wnt3a was detectedwith streptavidin-Dylight 800. A non-specific band was observed abovethe Wnt3a-V5 protein. Biotin-azide clicked palmitate was detected withstreptavidin-Dylight 800 (lower band). DMSO was used as negativecontrol. Lane 1: Without Alkyne palmitate; Lane 2: untreated control,DMSO+Alkyne palmitate; Lane 3: 100 nM Compound 51+Alkyne palmitate.

Results of the Soft Agar Assay are shown in Table 1 and FIGS. 5 to 7.

TABLE 1 Fifty percent colony growth inhibitory concentration (IC₅₀, μM)of Compound 51 on pancreatic cell lines AsPC-1 and HPAF-II. Resultsshown below are mean ± standard deviation (SD) from two independentexperiments. Test 1 Test 2 Mean Standard Com- IC₅₀ IC₅₀ IC₅₀ deviationMaximum pound Cell line (μM) (μM) (μM) (SD) inhibition 51 AsPC-1 0.0240.010 0.017 0.010 76% HPAF-II 0.008 0.010 0.009 0.001 97% CFPAC-1 0.0580.039 0.049 0.013 79%

The results of the MMTV-Wnt1 Mouse Model are shown in FIG. 2 and Table2:

TABLE 2 Day 14 Compound - % % Signif- dose TGI T/C T/C icance TRD NTRDVehicle — — — 0/8 0/8 Compound 68 0.375 37.5 *** 0/8 1/8 51-1 mg/KgCompound 67 0.383 38.3 *** 0/8 0/8 51-3 mg/Kg Compound 91 0.160 16.0 ***0/8 0/8 51-10 mg/Kg

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer, step, group of integers or group of steps but notto the exclusion of any other integer, step, group of integers or groupof steps.

All patents and patent applications mentioned throughout thespecification of the present invention are herein incorporated in theirentirety by reference.

The invention embraces all combinations of preferred and more preferredgroups and embodiments of groups recited above.

1. A compound of formula (I),

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof wherein: R₁ representsH; optionally substituted alkyl (wherein optional substituents includeone or more substituents each independently selected from C₁₋₆alkoxy,NH₂, —NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂); —C(O)Oalkyl; haloalkyl;haloalkoxy; or -alkylaryl; each R₂ independently represents H;optionally substituted alkyl (wherein optional substituents include oneor more substituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂); -alkylaryl; optionally substitutedcarbocyclyl (wherein optional substituents include one or moresubstituents each independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo); optionally substitutedheterocyclyl (wherein optional substituents include one or moresubstituents each independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,—C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl); —NHalkyl;—N(alkyl)₂; amino; hydroxyl; alkoxy or halo; n represents 0, 1 or 2; R₃represents H or alkyl; R₄ represents H or alkyl; R₅ represents H oralkyl; W and X each independently represent C═O; C═S; or CH₂; Yrepresents aryl; heteroaryl; optionally substituted carbocyclyl (whereinoptional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆haloalkoxy and halo); or optionally substituted heterocyclyl(wherein optional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl); and Z represents optionallysubstituted alkyl (wherein optional substituents include one or moresubstituents each independently selected from C₁₋₆alkoxy, NH₂,—NHC₁₋₃alkyl and —(C₁₋₃alkyl)₂); aryl; heteroaryl; -alkylaryl;-alkylheteroaryl; optionally substituted carbocyclyl (wherein optionalsubstituents include one or more substituents each independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy andhalo); optionally substituted heterocyclyl (wherein optionalsubstituents include one or more substituents each independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and—C(O)NHC₁₋₆alkyl); -alkylcarbocyclyl wherein carbocyclyl is optionallysubstituted (wherein optional substituents include one or moresubstituents each independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy and halo); -alkylheterocyclyl wherein heterocyclyl isoptionally substituted (wherein optional substituents include one ormore substituents each independently selected from C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl); -arylcarbocyclylwherein carbocyclyl is optionally substituted (wherein optionalsubstituents include one or more substituents each independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy and halo); or-arylheterocyclyl wherein heterocyclyl is optionally substituted(wherein optional substituents include one or more substituents eachindependently selected from C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, —C(O)C₁₋₆alkyland —C(O)NHC₁₋₆alkyl). 2-28. (canceled)
 29. A method of modulating WNTactivity comprising exposing a WNT protein or a WNT receptor to acompound according to claim
 1. 30. A method according to claim 29wherein the method is an in vivo method. 31-32. (canceled)
 33. A methodof treating a disease or condition associated with WNT pathway activitycomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (I)

or a pharmaceutically acceptable salt, solvate, polymorph, tautomer andstereoisomer thereof wherein, R₁represents H; optionally substitutedalkyl wherein optional substituents are one or more substituents eachindependently selected from C₁₋₆alkoxy, NH₂, —NH(C₁₋₃alkyl)₂;—C(O)Oalkyl; haloalkyl; haloalkoxy; or -alkylaryl; each R₂ independentlyrepresents H; optionally substituted alkyl wherein optional substituentsare one or more substituents each independently selected fromC₁₋₆alkoxy, NH₂, —NHC₁₋₃alkyl and —N(C₁₋₃alkyl)₂; -alkylaryl; optionallysubstituted carbocyclyl wherein optional substituents are one or moresubstituents each independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆haloalkoxy and halo; optionally substitutedheterocyclyl wherein optional substituents are one or more substituentseach independently selected from C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OC₁₋₆alkyl,—C(O)C₁₋₆alkyl and —C(O)NHC₁₋₆alkyl; —NHalkyl; —N(alkyl)₂; amino;hydroxyl; alkoxy or halo; n represents 1; R₃ represents H or alkyl; R₄represents H or alkyl; R₅ represents H or alkyl; W and X eachindependently represent C═O; C═S; or CH₂; Y represents optionallysubstituted phenyl or optionally substituted 6-membered heteroaryl; andZ represents optionally substituted aryl or optionally substitutedheteroaryl. 34-39. (canceled)
 40. A process for preparation of acompound of claim 1, wherein W and X each represent C═O, which processcomprises reaction of a compound of formula (II):

wherein R₁, R₂, R₂, n, R₃ and R₄ are as defined in claim 1, with acompound of formula (III)

or a protected derivative thereof, wherein R₅, Y and Z are as defined inclaim
 1. 41. The process of claim 40, wherein W and X each representCH₂, which process comprises conversion of the W and X groups ofcompounds of formula (I) from C═O groups into CH₂ groups.
 42. Theprocess of claim 40, wherein W and X each represent C═S, which processcomprises conversion of the W and X groups of compounds of formula (I)from C═O groups into C═S groups.
 43. The method of claim 33, wherein thedisease or condition is selected from the group consisting of cancer,fibrosis, stem cell and diabetic retinopathy, rheumatoid arthritis,psoriasis, and myocardial infarction.
 44. The method of claim 43,wherein the disease or condition is selected from the group consistingof cervical cancer, colon cancer, breast cancer, bladder cancer, headand neck cancer, gastric cancer, lung cancer, ovarian cancer, prostatecancer, thyroid cancer, non-small-cell lung cancer, chronic lymphocyticleukemia, mesothelioma, melanoma, pancreatic adenocarcinoma, basal cellcarcinoma, osteosarcoma, hepatocellular carcinoma, Wilm's tumor,medulloblastoma, pulmonary fibrosis, liver fibrosis, skin fibrosis,renal fibrosis, and diabetic retinopathy.
 45. The method of claim 33,wherein the compound of formula (I) is selected from the groupconsisting of: Compound ID Structure IUPAC Name 14

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)butanamide 24

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(oxazol-5-yl)phenyl)-4- oxobutanamide 25

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(oxazol-5-yl)phenyl)-4- oxobutanamide 26

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(thiazol-2-yl)pyridin-2- yl)butanamide 27

N-(4-(1H-imidazol-1- yl)phenyl)-4-(2-methyl-6,7- dihydropyrazoIo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 28

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(2-methylthiazol-4- yl)phenyl)-4-oxobutanamide 29

N-(4-(1-methyl-1H-pyrazol- 5-yl)phenyl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 32

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-(2-methylthiazol-4- yl)phenyl)-4-oxobutanamide 33

N-([1,1′-biphenyl]-4-yl)-4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 34

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-2- yl)phenyl)butanamide 35

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-3- yl)phenyl)butanamide 36

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyridin-4- yl)phenyl)butanamide 37

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyridazin-3- yl)phenyl]butanamide 38

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrimidin-4- yl)phenyl)butanamide 39

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyrimidin-5- yl)phenyl]butanamide 40

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[4-(pyrimidin-2- yl)phenyl]butanamide 41

N-([2,3′-bipyridin]-6′-yl)-4- (2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 42

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrazin-2- yl)phenyl)butanamide 43

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridin-3- yl)butanamide 44

44Synthesis of 4-(2-methyl- 6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo- N-(5-phenylpyridin-2- yl)butanamide 45

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridazin-3- yl)butanamide 46

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4- yl}-4-oxo-N-(5-phenylpyrimidin-2- yl)butanamide 47

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-phenylpyrazin-2- yl)butanamide 48

N-([2,3′-bipyridin]-5-yl)-4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 49

4-{2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4-yl}-4-oxo-N-[5-(pyridin-3- yl)pyridin-2-yl]butanamide 50

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyrazin-2-yl)pyridin-2- yl)butanamide 51

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyridin-3-yl)pyridazin- 3-yl)butanamide 52

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyridin-3-yl)pyrazin-2- yl)butanamide 53

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(3-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide 54

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(2-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide 55

N-(3-methoxy-[1,1′- biphenyl]-4-yl)-4-(2-methyl 6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 56

N-(2-methoxy-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 57

N-(2-fluorobiphenyl-4-yl)-4- (2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 58

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(2′-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide 59

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(3′-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide 60

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4′-methyl-[1,1′-biphenyl]-4-yl)- 4-oxobutanamide 61

N-(2′-methoxy-[1,1′- biphenyl]-4-yl)-4-(2-methyl6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 62

N-(3′-methoxy-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 63

N-(4′-methoxy-[1,1- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 64

N-(2′-fluoro-[1,1′-biphenyl]- 4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 65

N-(3′-fluoro-[1,1′-biphenyl]- 4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 66

N-(4′-fluorobiphenyl-4-yl)-4- (2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 67

4′-(4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxobutanamido)-[1,1′- biphenyl]-3-carboxylic acid 68

N,N-dimethyl-4′-(4-(2- methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamido)-[1,1′- biphenyl]-3-carboxamide69

N-(2′-amino-[1,1′-biphenyl]- 4-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 70

N-(3′-amino-[1,1′-biphenyl]- 4-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 71

N-(4′-amino-[1,1′-biphenyl]- 4-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 72

N-(3′-(dimethylamino)-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 73

4-(2-methyl-6.7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(3′-morpholinobiphenyl-4-yl)-4- oxobutanamide 74

N-(3′-acetamido-[1,1′- biphenyl]-4-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 83

N-(6-(3- chlorophenyl)pyridin-3-yl)-4- (2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 84

N-(6-(3-fluorophenyl)pyridin- 3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 85

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(m-tolyl)pyridin-3- yl)butanamide 86

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-methyl-6-phenylpyridin-3-yl)- 4-oxobutanamide 87

N-(6-(4-fluorophenyl)pyridin- 3-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 88

N-(6-(3- fluorophenyl)pyridazin-3-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 89

N-(5-(3-fiuorophenyl)pyridin- 2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 90

N-(5-(4-fluorophenyl)pyridin- 2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 91

N-(3-methyl-5-phenylpyridin- 2-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutana 92

N-(4-methyl-5-phenylpyridin- 2-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 93

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(m-tolyl)pyridin-2- yl)butanamide 94

N-(5-fluoro-2,3′-bipyridin-6′- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 95

N-(4-fluoro-2,3′-bipyridin-6′- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 96

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-methyl-[2,3′-bipyridin]-6′-yl)- 4-oxobutanamide 97

N-(6-(3- chlorophenyl)pyridazin-3-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 98

N-(6-(3- fluorophenyl)pyridazin-3-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 99

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(m-lolyl)pyridazin-3- yl)butanamide 100

N-[6-(4- chlorophenyl)pyridazin-3-yl]- 4-{2-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4- yl}-4-oxobutanamide 101

N-(6-(4- fluorophenyl)pyridazin-3-yl)- 4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 102

N-(6-(5-chloropyridin-3- yl)pyridazin-3-yl)-4-(2- methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 103

N-(6-(5-fluoropyridin-3- yl)pyridazin-3-yl)-4-(2- methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 104

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-(5-methylpyridin-3- yl)pyridazin-3-yl)-4- oxobutanamide 105

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(5- (trifluoromethyl)pyridin-3- yl)pyridazin-3-yl)butanamide 106

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-methyl-6-(pyridin-3- yl)pyridazin-3-yl)-4- oxobutanamide 107

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-(6-methylpyridin-3- yl)pyridazin-3-yl)-4- oxobutanamide 108

N-(5′-chloro-[2,3′-bipyridin]- 5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 109

N-(5′-fluoro-[2,3′-bipyridin]- 5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 110

N-(5′-methyl-2,3′-bipyridin-5- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 111

N-(3-fluoro-2,3′-bipyridin-5- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 112

N-(5′-amino-2,3′-bipyridin-5- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 113

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6′-methyl-[2,3′-bipyridin]-5-yl)- 4-oxobutanamide 114

N-(5′-chloro-[3,3′-bipyridin]- 6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 115

N-(5′-fluoro-[3,3′-bipyridin]- 6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 116

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[3,3′-bipyridin]-6-yl)- 4-oxobutanamide 117

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(piperazin-1- yl)phenyl)butanamide 118

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5′-(trifluoromethyl)-[3,3′- bipyridin]-6-yl)butanamide 119

N-(4-methyl-3,3′-bipyridin-6- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 120

N-(4,5′-dimethyl-3,3′- bipyridin-6-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 121

N-(6′-methyl-3,3′-bipyridin-6- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 122

N-(5-(5-fluoropyridin-3- yl)pyrazin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 123

N-(5-(3- fluorophenyl)pyrazin-2-yl)-4- (2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 124

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(5-methylpyridin-3- yl)pyrazin-2-yl)-4- oxobutanamide 125

N-(6-methyl-5-(pyridin-3- yl)pyrazin-2-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 126

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(m-tolyl)pyrazin-2- yl)butanamide 127

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyridin-3- yl)pyrazin-2-yl)-4- oxobutanamide 128

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyrazin-2- yl)pyridin-2-yl)-4- oxobutanamide 129

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(4-(pyrazin-2- yl)phenyl)butanamide 139

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-phenylpyridazin-3- yl)butanamide 140

N-(2,3′-bipyridin-5-yl)-4-(2,6- dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 141

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyridin-3-yl)pyridazin- 3-yl)butanamide 142

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[3,3′-bipyridin]-6-yl)- 4-oxobutanamide 143

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-methyl-[2,3′-bipyridin]-6′-yl)- 4-oxobutanamide 144

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-methyl-[2,3′-bipyridin]-5-yl)- 4-oxobutanamide 145

N-([2,3′-bipyridin]-5-yl)-2- methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 146

2-methyl-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4-oxo- N-(6-phenylpyridazin-3- yl)butanamide 147

N-([3,3′-bipyridin]-6-yl)-2- methyl-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 148

N-(4-methyl-2,3′-bipyridin-6′- yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 149

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(5-methylpyrazin-2- yl)pyridin-2-yl)-4- oxobutanamide 150

2-methyl-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′- methyl-[2,3′-bipyridin]-5-yl)-4-oxobutanamide 151

2-methyl-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5- (6-methylpyrazin-2- yl)pyridin-2-yl)-4-oxobutanamide 152

2-methyl-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′- methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide 153

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(5-(pyrimidin-5-yl)pyridin- 2-yl)butanamide 154

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyrimidin-5-yl)pyridin- 3-yl)butanamide 155

N-(2-fluorobiphenyl-4-yl)-4- (2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 156

N-(5-fluoro-6-phenylpyridin- 3-yl)-4-(2-methyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 157

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-(6-methylpyrazin-2- yl)pyridin-2-yl)-4- oxobutanamide 158

N-(3-fluoro-5′-methyl-[2,3′- bipyridin]-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 160

(S)-4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′- methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide 161

(R)-4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-(5′- methyl-[3,3′-bipyridin]-6-yl)-4-oxobutanamide 162

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-fluoro-[2,3′-bipyridin]-5-yl)- 4-oxobutanamide 163

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5′-fluoro-[3,3′-bipyridin]-6-yl)- 4-oxobutanamide 164

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(5-fluoro-[2,3′-bipyridin]-6′-yl)- 4-oxobutanamide 165

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4-fluoro-[3,3′-bipyridin]-6-yl)- 4-oxobutanamide 166

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo-N-(6-(pyrazin-2-yl)pyridin-3- yl)butanamide 167

4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(6-(5-fluoropyridin-3- yl)pyridazin-3-yl)-4- oxobutanamide 168

N-(3,5′-dimethyl-[2,3′- bipyridin]-5-yl)-4-(2-methyl-6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide 169

(S)-N-([3,3′-bipyridin]-6-yl)- 4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 170

(R)-N-([3,3′-bipyridin]-6-yl)- 4-(2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide 171

N-([2,3′-bipyridin]-6′-yl)-4- (2,6-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-4- oxobutanamide


46. The method of claim 33, wherein R₁ represents H, methyl, ethyl,—C(O)OMe, CF₃ or OMe.
 47. The method of claim 33, wherein each R₂independently represents H or alkyl.
 48. The method of claim 33, whereineach R₂ independently represents H.
 49. The method of claim 33, whereinR₃ represents H.
 50. The method of claim 33, wherein R₄ represents H.51. The method of claim 33, wherein R₅ represents H.
 52. The method ofclaim 33, wherein W and X each represent C═O.
 53. The method of claim33, wherein Y represents phenyl.
 54. The method of claim 33, wherein Yis substituted by one or more substituents each independently selectedfrom C₁₋₆ alkyl, C₁₋₆alkoxy, halo and C₁₋₆haloalkyl.
 55. The method ofclaim 33, wherein Z represents aryl or heteroaryl.